Landmark articles

1902

Bateson, W., Saunders, E.R. :

Experimental studies in the physiology of heredity. Part III. The facts of heredity in the light of Mendel's discovery Reports to the Evolution Committee of the Royal Society 1:125-160, 1902.

Why is this an OMIA landmark paper? It is the second of two adjacent papers (the other being Bateson and Saunders, 1902; pages 87-124) containing the very first reports of Mendelian inheritance in domesticated animals. In addition to the five Mendelian poultry traits reported in the preceding paper (Bateson and Saunders, 1902; pages 87-124), this paper also reported polled in cattle (OMIA 000483-9913) as being a Mendelian trait. In addition, Bateson and Saunders speculated (correctly) that the failure of the Andalusian chicken to breed true is because its breed-standard colour is due to heterozygosity (OMIA 001154-9031). This paper is also of significance because it introduced three important new words: allelomorph (now allele), heterozygote and homozygote.

Bateson, W., Saunders, E.R. :

Experimental studies in the physiology of heredity. Part II. Poultry Reports to the Evolution Committee of the Royal Society 1:87-124, 1902.

Why is this an OMIA landmark paper? It is first of two adjacent papers (the other being Bateson and Saunders, 1902; pages 125-160) that first reported Mendelian inheritance in animals. This paper reported five Mendelian poultry traits, namely Pea comb (OMIA 000782-9031), Rose comb (OMIA 000884-9031), polydactyly (OMIA 000810-9031), shank colour (OMIA 001449-9031), and white plumage (dominant white) (OMIA 000373-9031).

1905

Bateson, W., Punnett, R.C. :

Experimental studies in the physiology of heredity. Poultry. Reports to the Evolution Committee of the Royal Society 2:99-119, 1905.

Why is this an OMIA Landmark paper? It is the first to report that "walnut" comb in chickens is the phenotype that results from having the dominant Rose comb allele at the Rose comb locus, and the dominant Pea comb allele at the Pea comb locus, i.e. walnut comb results from the interaction of dominant alleles at two separate loci. Three years later, Bateson (1907; Science 26: 649-660) coined the term "epistatic" to describe such interactions. Having made this breakthrough, the authors then went on to provide the first report of a 9:3:3:1 two-locus Mendelian ratio involving the Pea comb and Rose comb loci. This paper also reports that the "blue" Andalusian feather phenotype results from heterozygosity at a plumage locus.

Hurst, C.C. :

Experiments with poultry. Reports to the Evolution Committee of the Royal Society 2:131-154, 1905.

Why is this an OMIA Landmark paper? It adds two new examples of Mendelian inheritance in chickens, namely feathered shanks and crested head.

1907

Bateson, W. :

Facts limiting the theory of heredity. Science 26:649-60, 1907. Pubmed reference: 17796786. DOI: 10.1126/science.26.672.649.

Why is this an OMIA Landmark paper? It is the paper in which the term "epistatic" was created to describe interactions between alleles at different loci. Significantly, this concept was introduced in the context of Walnut comb in chickens resulting from the interaction between the loci for Pea comb and Rose comb (see Bateson et al., 1905, above)

1917

Goodale, H.D. :

Crossing-over in the sex chromosome of the male fowl. Science 46:213 only, 1917. Pubmed reference: 17782267. DOI: 10.1126/science.46.1183.213.

Why is this an OMIA landmark paper? It is the first report of crossing-over in non-laboratory animals. Realising that sex-linked loci should show recombination in the homogametic sex, Goodlale reports the occurrence of recombinant offspring with respect to three Z-linked loci, namely barring (OMIA 000102-9031), silver (OMIA 000915-9031) and dominant white (OMIA 000373-9031). No actual data are reported, and hence no estimate of recombination fraction is provided.

1921

Haldane, J.B.S. :

Linkage in poultry. Science 54:663 only, 1921. Pubmed reference: 17816160. DOI: 10.1126/science.54.1409.663.

Why is this an OMIA landmark paper? It provides the first estimate of recombination fraction between loci in farm animals. Noting that sex-linked loci should show recombination in the homogametic sex, Haldane chose to study two well-known Z-linked genes, namely barring (OMIA 000102-9031) and silver feathers (OMIA 000915-9031) by crossing a Brown Leghorn rooster (bs/bs) with a Rhode Island Red hen (BS), and then mating the F1 males with Rhode Island Red hens. The estimated recombination fraction was 34.6%. Puzzlingly, Haldane does not refer to Goodale's earlier (1917) report in the same journal, involving a similar type of cross.

1928

Serebrovsky, A.S., Petrov, S.G. :

A case of close autosomal linkage in the fowl Journal of Heredity 19:305-306, 1928.

Why is this an OMIA Landmark paper? It presents the first-ever autosomal linkage group for any domesticated animal species. The two loci were Creeper (OMIA 000006-9031) and Rose comb (OMIA 000884-9031), with an estimated 8% recombination.

1953

Eldridge, F.E., Atkeson, F.W. :

Streaked hairlessness in Holstein-Friesian cattle. A sex-linked lethal character Journal of Heredity 44:265-271, 1953.

Why is this an OMIA Landmark paper? It is the first paper to report an X-linked trait in cattle, thereby being (as the authors reported) "the first character to be reported in dairy cattle for which the causative gene can be quite definitely located on a specific chromosome" (because of their data supporting X-linked inheritance) and consequently "the gene for streaked hairlessness becomes a marker for one linkage group, and thus is the first step towards building a chromosome map for cattle".

1987

Ricketts, M.H., Simons, M.J., Parma, J., Mercken, L., Dong, Q., Vassart, G. :

A nonsense mutation causes hereditary goitre in the Afrikander cattle and unmasks alternative splicing of thyroglobulin transcripts Proc Natl Acad Sci U S A 84:3181-4, 1987. Pubmed reference: 3472203. DOI: 10.1073/pnas.84.10.3181.

Why is this an OMIA landmark paper? It is the very first report of a causal mutation in domesticated non-laboratory animals. The discovery was made possible by the specific clinical signs, which suggested only one possible candidate gene, namely the TG gene, encoding thyroglobulin.

1989

Evans, J.P., Brinkhous, K.M., Brayer, G.D., Reisner, H.M., High, K.A. :

Canine hemophilia B resulting from a point mutation with unusual consequences. Proc Natl Acad Sci U S A 86:10095-9, 1989. Pubmed reference: 2481310. DOI: 10.1073/pnas.86.24.10095.

Why is this an OMIA Landmark paper? It provides the first case of a canine Mendelian disorder to be characterised at the DNA level, in this case a missense mutation (c.1477G>A; p. Gly379Glu) in the canine F9 gene. Unusually for a missense mutation, the result is no functional factor IX (possibly because the amino-acid substitution occurs in a highly conserved domain, any changes in which are likely to have a major effect on tertiary structure of the peptide).

1991

Fujii, J., Otsu, K., Zorzato, F., Deleon, S., Khanna, V.K., Weiler, J.E., O'Brien, P.J., MacLennan, D.H. :

Identification of a Mutation in Porcine Ryanodine Receptor Associated with Malignant Hyperthermia Science 253:448-51, 1991. Pubmed reference: 1862346. DOI: 10.1126/science.1862346.

Why is this an OMIA landmark paper? It was the first report of the causal mutation of one of the most-investigated and economically-important disorders to have occurred in domesticated animals. Extensive comparative mapping between humans and pigs eventually suggested the RYR1 gene encoding the ryanodine receptor as a very likely candidate gene. It turned out to be a huge gene (120 kb), the sequencing of which was a mammoth task at that time (late 1980s, early 1990s). These authors were the first to show that the smallest possible mutation (a single-base missense mutation) that changed just one amino acid in a very large molecule comprising 5,035 amino acids, was the cause of a disorder that had been a major financial burden for the global pig industry for several decades.

Gillard, E.F., Otsu, K., Fujii, J., Khanna, V.K., de Leon, S., Derdemezi, J., Britt, B.A., Duff, C.L., Worton, R.G., MacLennan, D.H. :

A substitution of cysteine for arginine 614 in the ryanodine receptor is potentially causative of human malignant hyperthermia. Genomics 11:751-5, 1991. Pubmed reference: 1774074. DOI: 10.1016/0888-7543(91)90084-r.

Why is this an OMIA Landmark paper? Because it provides the first example of the molecular basis of a human inherited disorder (malignant hyperthermia) being discovered via the discovery of the molecular basis of the homologous disorder in a non-laboratory animal, namely pigs (see Fujii et al., 1991; previous landmark paper). It also provides the first published example of an homologous inherited disorder in humans and in non-laboratory animals (in this case, pigs) being due to exactly the same base substitution (leading to the same amino-acid substitution) in the equivalent site of a gene, namely the RYR1 gene (c.1843C>T, p.Arg615Cys in pigs, Fujii et al., 1991, see previous Landmark paper; and c.1840C>T; p.Arg614Cys in humans, Gillard et al., 1991). [FN thanks Hamutal Mazrier for suggesting that the first discovery of the same mutation causing the same disorder in humans and non-laboratory animals should be a Landmark]

Matsumine, H., Herbst, M.A., Ou, S.H.I., Wilson, J.D., Mcphaul, M.J. :

Aromatase messenger RNA in the extragonadal tissues of chickens with the Henny-Feathering trait is derived from a distinctive promoter structure that contains a segment of a retroviral long terminal repeat - Functional organization of the Sebright, Leghorn, and Campine aromatase genes. J Biol Chem 266:19900-7, 1991. Pubmed reference: 1939054.

Why is this an OMIA landmark paper? It is the first report of an insertion mutation in non-laboratory domesticated animals.

1993

Georges, M., Drinkwater, R., King, T., Mishra, A., Moore, S.S., Nielsen, D., Sargeant, L.S., Sorensen, A., Steele, M.R., Zhao, X.Y., Womack, J.E., Hetzel, J. :

Microsatellite mapping of a gene affecting horn development in Bos-taurus. Nature Genetics 4:206-210, 1993. Pubmed reference: 8348158. DOI: 10.1038/ng0693-206.

Why is this an OMIA landmark paper? It is the second example of the fruits of the development of linkage maps that covered, in essence, the whole genome. In this particular case, nine paternal half-sib families were genotyped for 233 microsatellites (and 38 minisatellities) covering most regions of most chromosomes. A linkage analysis revealed the polled/horned locus to be linked to two markers on bovine chromosome 1 (BTA1). The recombination fraction was frustratingly large (13%), but in 1993, this result was sufficiently important and novel to warrant publication in Nature Genetics!

Georges, M., Dietz, A.B., Mishra, A., Nielsen, D., Sargeant, L.S., Sorensen, A., Steele, M.R., Zhao, X.Y., Leipold, H.W., Womack, J.E., Lathrop, M. :

Microsatellite Mapping of the Gene Causing Weaver Disease in Cattle Will Allow the Study of an Associated Quantitative Trait Locus Proc Natl Acad Sci U S A 90:1058-62, 1993. Pubmed reference: 8430074. DOI: 10.1073/pnas.90.3.1058.

Why is this an OMIA landmark paper? It is the first fruit of the development of genome-wide linkage maps comprising hundreds of microsatellite markers. 33 affected animals and their close relatives were each genotyped for 233 microsatellite markers (and other markers) that covered, in essence, every region of every chromosome. Linkage analysis revealed that the Weaver locus was linked to just one microsatellite marker, with a recombination fraction of 3%. Interestingly, at that stage, the linkage group to which this marker belonged could not been assigned to a chromosome. The best the authors were able to do was to assign the marker by somatic-cell hybridisation to synteny group U13. This synteny group was eventually shown to be located on bovine chromosome 4 (BTA4).

Kay, M.A., Rothenberg, S., Landen, C.N., Bellinger, D.A., Leland, F., Toman, C., Finegold, M., Thompson, A.R., Read, M.S., Brinkhous, K.M., Woo, S.L.C. :

In Vivo Gene Therapy of Hemophilia-B - Sustained Partial Correction in Factor-IX-Deficient Dogs Science 262:117-9, 1993. Pubmed reference: 8211118. DOI: 10.1126/science.8211118.

Why is this an OMIA Landmark paper? It reported the first use of gene therapy to alleviate the effects of an inherited disorder in OMIA species. In this case, infusion of recombinant retroviral vectors containing cDNA for canine factor IX into the liver of dogs affected with haemophilia B resulted in partial alleviation of the disorder. [FN thanks Hamutal Mazrier for suggestion that the first case of gene therapy in OMIA species is worthy of an OMIA Landmark entry]

Montgomery, G.W., Crawford, A.M., Penty, J.M., Dodds, K.G., Ede, A.J., Henry, H.M., Pierson, C.A., Lord, E.A., Galloway, S.M., Schmack, A.E., Sise, J.A., Swarbrick, P.A., Hanrahan, V., Buchanan, F.C., Hill, D.F. :

The Ovine Booroola Fecundity Gene (FecB) Is Linked to Markers from a Region of Human Chromosome-4q Nature Genetics 4:410-414, 1993. Pubmed reference: 8401591. DOI: 10.1038/ng0893-410.

Why is this an OMIA landmark paper? It was the first to identify markers linked to the famed Booroola fecundity gene, which had been extensively studied for more than a decade. Although the markers were microsatellities, a linkage map of sheep microsatellites was not then available. Thus, the markers themselves provided no direct clue to the gene's location in the sheep genome. By a somewhat circuitous route, the authors discovered that the Booroola gene was also linked to an RFLP for the SPP1 gene, which in humans is on chromosome HSA4q. This explains why the title of the paper talks in terms of mapping a sheep gene to a human chromosome, but not to a sheep chromosome. Interestingly, this emphasis on mapping to a human chromosome was sufficient for Dr Victor McKusick to create and entry in the human catalogue OMIM entitled "FECUNDITY GENE, BOOROOLA, OF SHEEP, HOMOLOG OF" in September 1993.

1995

Klungland, H., Vage, D.I., Gomezraya, L., Adalsteinsson, S., Lien, S. :

The role of melanocyte-stimulating hormone (msh) receptor in bovine coat color determination Mamm Genome 6:636-9, 1995. Pubmed reference: 8535072. DOI: 10.1007/BF00352371.

Whay is this an OMIA Landmark paper? It was the first published account of the molecular basis of coat colour alleles in any non-laboratory animal species.

1996

Charlier, C., Farnir, F., Berzi, P., Vanmanshoven, P., Brouwers, B., Vromans, H., Georges, M. :

Identity-by-descent mapping of recessive traits in livestock - application to map the bovine syndactyly locus to chromosome 15 Genome Res 6:580-9, 1996. Pubmed reference: 8796345. DOI: 10.1101/gr.6.7.580.

Why is this an OMIA Landmark paper? It was the first report of the use of identity-by-descent mapping, which involves ("searching for shared homozygous haplotypes among affected individuals") to map a single-locus disorder in domestic animals. This particular case involved a genome scan with 213 microsatellite markers genotyped on just 12 syndactylous (mule foot) animals and on a DNA pool of 10 unrelated non-affected animals from the same breed. A single region on each three chromosomes were significant. Genotyping an additional 29 animals from the same pedigree, followed by a conventional linkage analysis, mapped the disorder to the telomeric end of chromosome BTA15.

Johansson Moller, M., Chaudhary, R., Hellmén, E., Höyheim, B., Chowdhary, B., Andersson, L. :

Pigs with the dominant white coat color phenotype carry a duplication of the KIT gene encoding the mast/stem cell growth factor receptor. Mamm Genome 7:822-30, 1996. Pubmed reference: 8875890. DOI: 10.1007/s003359900244.

Why is this an OMIA landmark paper? It is an excellent example of the power of comparative genomics. Building on strong evidence that the KIT gene was a comparative positional candidate for dominant white spotting in pigs, these authors discovered that this porcine trait is, indeed, due to a mutation in the porcine KIT gene.

1997

Grobet, L., Martin, L.J.R., Poncelet, D., Pirottin, D., Brouwers, B., Riquet, J., Schoeberlein, A., Dunner, S., Menissier, F., Massabanda, J., Fries, R., Hanset, R., Georges, M. :

A deletion in the bovine myostatin gene causes the double-muscled phenotype in cattle Nature Genetics 17:71-74, 1997. Pubmed reference: 9288100. DOI: 10.1038/ng0997-71.

Why is this an OMIA landmark paper? It was the first of three papers, published almost simultaneously, to report causal mutations for the famed double-muscling trait in Belgian Blue and other cattle breeds. A knockout mutation of the myostatin gene (MSTN) in mice, causing a very similar phenotype, provided the comparative positional candidate gene that led to the discovery of causal mutations in the bovine MSTN gene.

Kambadur, R., Sharma, M., Smith, T.P.L., Bass, J.J. :

Mutations in myostatin (GDF8) in double-muscled Belgian Blue and Piedmontese cattle Genome Res 7:910-6, 1997. Pubmed reference: 9314496. DOI: 10.1101/gr.7.9.910.

Why is this an OMIA landmark paper? It was the second of three papers, published almost simultaneously, to report mutations in the bovine myostatin gene as being causal of double muscling in cattle.

McPherron, A.C., Lee, S.J. :

Double muscling in cattle due to mutations in the myostatin gene Proc Natl Acad Sci U S A 94:12457-61, 1997. Pubmed reference: 9356471. DOI: 10.1073/pnas.94.23.12457.

Why is this an OMIA landmark paper? It was the third of three papers, published almost simultaneously, to report mutations in the bovine myostatin gene as being causal of double muscling in cattle.

Tan, P., Allen, J.G., Wilton, S.D., Akkari, P.A., Huxtable, C.R., Laing, N.G. :

A splice-site mutation causing ovine McArdle's-disease Neuromuscul Disord 7:336-42, 1997. Pubmed reference: 9267848. DOI: 10.1016/s0960-8966(97)00062-x.

Why is this an OMIA Landmark paper? To FN's knowledge, it is the first publication in which a disorder is described for the first time in a particular species AND a likely causal variant is reported for that disorder. (If anyone knows of an earlier example, please let FN know!)

2000

Galloway, S.M., McNatty, K.P., Cambridge, L.M., Laitinen, M.P.E., Juengel, J.L., Jokiranta, T.S., McLaren, R.J., Luiro, K., Dodds, K.G., Montgomery, G.W., Beattie, A.E., Davis, G.H., Ritvos, O. :

Mutations in an oocyte-derived growth factor gene (BMP15) cause increased ovulation rate and infertility in a dosage-sensitive manner Nature Genetics 25:279-283, 2000. Pubmed reference: 10888873. DOI: 10.1038/77033.

Why is this an OMIA landmark paper? It was the first report of likely causal variants for inherited fecundity/prolificacy. In this case, the variants were the result of mutations in the X-linked BMP15 gene, encoding bone morphogenic protein 15. The authors showed that the X-linked Fecundity-Inverdale (OMIA 000386-9940) and Fecundity-Hannah (OMIA 001350-9940) prolificacy traits are due to mutations in BMP15.

Milan, D., Jeon, J.T., Looft, C., Amarger, V., Robic, A., Thelander, M., Rogel-Gaillard, C., Paul, S., Iannuccelli, N., Rask, L., Ronne, H., Lundstrom, K., Reinsch, N., Gellin, J., Kalm, E., Le, Roy, P., Chardon, P., Andersson, L. :

A mutation in PRKAG3 associated with excess glycogen content in pig skeletal muscle Science 288:1248-51, 2000. Pubmed reference: 10818001. DOI: 10.1126/science.288.5469.1248.

Why is this an OMIA Landmark paper? It is the first example of positional cloning in domestic animals. Importantly, it was achieved without the aid of any genome assembly, because none existed at that time. Solely on the basis of accurate mapping of the trait (RN) in the species of interest (pig), Milan et al. were able to narrow down the candidate region to a single gene (PRKAG3) that was hitherto not known in any species, and then to identify the causative (missense) mutation in that gene.

2001

Aronovich, E.L., Johnston, J.M., Wang, P., Giger, U., Whitley, C.B. :

Molecular basis of mucopolysaccharidosis type IIIB in emu (Dromaius novaehollandiae): An avian model of Sanfilippo syndrome type B Genomics 74:299-305, 2001. Pubmed reference: 11414757. DOI: 10.1006/geno.2001.6552.

Why is this an OMIA landmark paper? It is an early example of a single paper in which the first report of a disorder (apart from a conference abstract in 1997) is combined with a description of the causal mutation, in a non-conventional species. The speed of discovery was greatly enhanced by clear clinical signs and the lack of an enzyme immediately suggesting a strong candidate gene.

Charlier, C., Segers, K., Karim, L., Shay, T., Gyapay, G., Cockett, N., Georges, M. :

The callipyge mutation enhances the expression of coregulated imprinted genes in cis without affecting their imprinting status Nature Genetics 27:367-369, 2001. Pubmed reference: 11279514. DOI: 10.1038/86856.

Why is this an OMIA landmark article? It is a key report of the very interesting epigenetics involved in the callipyge phenotype, a form of ovine muscular hypertrophy. The callipyge phenotype is seen only in heterozygotes that have inherited the allele from their sire – an unusual form of inheritance called polar over-dominance, a new term introduced for this phenotype. To summarise this and later research: the mutation is a base substitution in a non-coding section of a 90-kb region of DNA that contains six genes: DLK1, DAT, and PEG11 have paternal allele-specific expression whereas GTL2, PEG11AS and MEG8 are expressed from the maternal allele. When an animal inherits the callipyge mutation from its sire but not its dam, the mutation increases the expression of the DLK1 and PEG11 genes on the same (paternal) chromosome; the mutation is said to be cis-acting. The increased expression of these two genes is associated with the muscle hypertrophy. of the callipyge trait.

Mealey, KL., Bentjen, SA., Gay, JM., Cantor, GH. :

Ivermectin sensitivity in collies is associated with a deletion mutation of the mdr1 gene. Pharmacogenetics 11:727-33, 2001. Pubmed reference: 11692082. DOI: 10.1097/00008571-200111000-00012.

Why is this an OMIA Landmark paper? It is the first to document a likely causal variant for adverse reaction to certain drugs in dogs.

Mulsant, P., Lecerf, F., Fabre, S., Schibler, L., Monget, P., Lanneluc, I., Pisselet, C., Riquet, J., Monniaux, D., Callebaut, I., Cribiu, E., Thimonier, J., Teyssier, J., Bodin, L., Cognie, Y., Chitour, N., Elsen, J.M. :

Mutation in bone morphogenetic protein receptor-IB is associated with increased ovulation rate in Booroola Merino ewes Proceedings of the National Academy of Sciences of the United States of America 98:5104-5109, 2001. Pubmed reference: 11320249. DOI: 10.1073/pnas.091577598.

Why is this an OMIA landmark paper? It was the second of three papers published almost simultaneously reporting the same causal mutation of the extensively-studied Booroola fecundity gene, namely a missense mutation (Q249R) in BMPR-IB, the gene that encodes the receptor for bone morphogenetic protein IB.

Souza, C.J.H., MacDougall, C., Campbell, B.K., McNeilly, A.S., Baird, D.T. :

The Booroola (FecB) phenotype is associated with a mutation in the bone morphogenetic receptor type 1 B (BMPR1B) gene J Endocrinol 169:R1-6, 2001. Pubmed reference: 11312159. DOI: 10.1677/joe.0.169r001.

Why is this an OMIA landmark paper? It was the third of three papers published almost simultaneously, reporting the causative mutation of the extensively-studied Booroola fecundity gene as being a missense mutation (Q249R) in BMPR-IB, the gene that encodes the receptor for bone morphogenetic protein IB.

Wilson, T., Wu, X.Y., Juengel, J.L., Ross, I.K., Lumsden, J.M., Lord, E.A., Dodds, K.G., Walling, G.A., McEwan, J.C., O'Connell, A.R., McNatty, K.P., Montgomery, G.W. :

Highly prolific Booroola sheep have a mutation in the intracellular kinase domain of bone morphogenetic protein IB receptor (ALK-6) that is expressed in both oocytes and granulosa cells Biol Reprod 64:1225-35, 2001. Pubmed reference: 11259271. DOI: 10.1095/biolreprod64.4.1225.

Why is this an OMIA landmark paper? It was the first of three papers published almost simultaneously, each of which reported the causal mutation of the extensively-studied Booroola fecundity gene to be a missense mutation (Q249R) in BMPR-IB, the gene that encodes the receptor for bone morphogenetic protein IB.

2002

Freking, B.A., Murphy, S.K., Wylie, A.A., Rhodes, S.J., Keele, J.W., Leymaster, K.A., Jirtle, R.L., Smith, T.P.L. :

Identification of the single base change causing the callipyge muscle hypertrophy phenotype, the only known example of polar overdominance in mammals Genome Research 12:1496-1506, 2002. Pubmed reference: 12368241. DOI: 10.1101/gr.571002.

Why is this an OMIA landmark paper? It is one of two papers (the other being Smit et al., 2003) to report a most unusual (and challenging to discover) type of causal mutation. As summarised by Nicholas (2010; Introduction to Veterinary Genetics, Wiley-Blackwell, Oxford; p. 202), "The mutation is a base substitution in a non-coding section of a 90-kb region of DNA that contains six genes: DLK1, DAT, and PEG11 have paternal allele-specific expression whereas GTL2, PEG11AS and MEG8 are expressed from the maternal allele. When an animal inherits the callipyge mutation from its sire but not its dam, the mutation increases the expression of the DLK1 and PEG11 genes on the same (paternal) chromosome; the mutation is said to be cis-acting. The increased expression of these two genes is associated with the muscle hypertrophy of the callipyge trait."

2003

Smit, M., Segers, K., Carrascosa, L.G., Shay, T., Baraldi, F., Gyapay, G., Snowder, G., Georges, M., Cockett, N., Charlier, C. :

Mosaicism of Solid Gold supports the causality of a noncoding A-to-G transition in the determinism of the callipyge phenotype Genetics 163:453-6, 2003. Pubmed reference: 12586730. DOI: 10.1093/genetics/163.1.453.

Why is this an OMIA landmark paper? It is one of two papers (the other being Freking et al., 2002) to report a most unusual (and challenging to discover) type of causal mutation. As summarised by Nicholas (2010; Introduction to Veterinary Genetics, Wiley-Blackwell, Oxford; p. 202), "The mutation is a base substitution in a non-coding section of a 90-kb region of DNA that contains six genes: DLK1, DAT, and PEG11 have paternal allele-specific expression whereas GTL2, PEG11AS and MEG8 are expressed from the maternal allele. When an animal inherits the callipyge mutation from its sire but not its dam, the mutation increases the expression of the DLK1 and PEG11 genes on the same (paternal) chromosome; the mutation is said to be cis-acting. The increased expression of these two genes is associated with the muscle hypertrophy of the callipyge trait."

Van Laere, A.S., Nguyen, M., Braunschweig, M., Nezer, C., Collette, C., Moreau, L., Archibald, A.L., Haley, C.S., Buys, N., Tally, M., Andersson, G., Georges, M., Andersson, L. :

A regulatory mutation in IGF2 causes a major QTL effect on muscle growth in the pig. Nature 425:832-6, 2003. Pubmed reference: 14574411. DOI: 10.1038/nature02064.

Why is the an OMIA Landmark paper? It was the first report in any species (including mice and humans) of a non-coding mutation as the basis for a QTL. In other words, it was the first non-coding QTN to be reported in any species. In a subsequent study, Markljung et al. (2009; PLoS Biol 7:e1000256) were able to identify the nuclear protein that is binding the wild-type sequence but not the mutant form. It turned out to be a previously unknown protein, which they named ZBED6 (see http://omia.angis.org.au/gene389754429/), that is unique to placental mammals and has evolved from a domesticated DNA transposon.

2005

Lohi, H., Young, E.J., Fitzmaurice, S.N., Rusbridge, C., Chan, E.M., Vervoort, M., Turnbull, J., Zhao, X.C., Ianzano, L., Paterson, A.D., Sutter, N.B., Ostrander, E.A., André, C., Shelton, G.D., Ackerley, C.A., Scherer, S.W., Minassian, B.A. :

Expanded repeat in canine epilepsy. Science 307:81, 2005. Pubmed reference: 15637270. DOI: 10.1126/science.1102832.

Why is this an OMIA Landmark paper? It presents the first report of an inherited disorder in domesticated animals being shown to be due to an expanded repeat. In this particular case, affected dogs as have 19 to 26 copies of a sequence of 12 nucleotides (12-mer; dodecamer) in the canine EPM2B gene (now called NHLRC1). This repeat occurs only twice or three times in normal dogs of a wide range of breeds.

Lyons, LA., Imes, DL., Rah, HC., Grahn, RA. :

Tyrosinase mutations associated with Siamese and Burmese patterns in the domestic cat (Felis catus). Anim Genet 36:119-26, 2005. Pubmed reference: 15771720. DOI: 10.1111/j.1365-2052.2005.01253.x.

Why is this an OMIA Landmark paper? It was the first of two 2005 papers that independently discovered the molecular basis of the "trade-mark" genes for pointing in Siamese and Burmese cats.

Schmidt-Küntzel, A., Eizirik, E., O'Brien, S.J., Menotti-Raymond, M. :

Tyrosinase and tyrosinase related protein 1 alleles specify domestic cat coat color phenotypes of the albino and brown loci. J Hered 96:289-301, 2005. Pubmed reference: 15858157. DOI: 10.1093/jhered/esi066.

Why is the an OMIA Landmark paper? It is the second of two 2005 papers that independently discovered the molecular basis of the "trade-mark" genes for pointing in Siamese and Burmese cats.

2006

Juling, K., Schwarzenbacher, H., Williams, JL., Fries, R. :

A major genetic component of BSE susceptibility. BMC Biol 4:33, 2006. Pubmed reference: 17014722. DOI: 10.1186/1741-7007-4-33.

Why is this an OMIA landmark paper? It showed, for the first time in cattle, a strong association between polymorphism in the PRNP locus and susceptibility to spongiform encephalopathy.

Li, FY., Cuddon, PA., Song, J., Wood, SL., Patterson, JS., Shelton, GD., Duncan, ID. :

Canine spongiform leukoencephalomyelopathy is associated with a missense mutation in cytochrome b. Neurobiol Dis 21:35-42, 2006. Pubmed reference: 16026996. DOI: 10.1016/j.nbd.2005.06.009.

Why is this an OMIA landmark paper? It is the first report of an animal disorder due to a spontaneous mutation in mitochondrial DNA (mtDNA). The paper is also important because it is an early example of a single paper combining the first report of a disorder in a particular species with a description of its likely causal variant; in this case, a missense mutation in the mtDNA-encoded cytochrome b gene.

Mellersh, CS., Boursnell, ME., Pettitt, L., Ryder, EJ., Holmes, NG., Grafham, D., Forman, OP., Sampson, J., Barnett, KC., Blanton, S., Binns, MM., Vaudin, M. :

Canine RPGRIP1 mutation establishes cone-rod dystrophy in miniature longhaired dachshunds as a homologue of human Leber congenital amaurosis. Genomics 88:293-301, 2006. Pubmed reference: 16806805. DOI: 10.1016/j.ygeno.2006.05.004.

Why is this an OMIA landmark paper? It is an early example of identification of a causal mutation by the comparative positional candidate-gene approach. In this case, a linkage analysis with 108 microsatellite markers identified one marker very closely linked to the disorder locus (recombination fraction = 0.0). The newly available canine sequence genome assembly enabled the authors to locate this marker, and hence the disorder locus, at 42.11Mb on canine choromosome 15 (CFA15). Comparative mapping revealed that this region of CFA15 corresponds to human chromosome HSA14q11, which contains a very strong candidate gene for this disorder, namely the gene encoding retinitis pigmentosa GTPase regulator-interacting protein 1 (RPGRIP1). The canine homologue of this gene was identified in the canine genome assembly, and sequencing of this gene in affecteds and normals revealed the causative mutation, a 44-bp insertion in exon 2, which creates a premature stop codon.

Rompler, H., Rohland, N., Lalueza-Fox, C., Willerslev, E., Kuznetsova, T., Rabeder, G., Bertranpetit, J., Schoneberg, T., Hofreiter, M. :

Nuclear gene indicates coat-color polymorphism in mammoths. Science 313:62, 2006. Pubmed reference: 16825562. DOI: 10.1126/science.1128994.

Why is this an OMIA landmark paper? In a novel manner, it shows the power of comparative genomics. Having obtained workable quantities of DNA from a long-extinct woolly mammoth, the authors sequenced it for one of the classic coat-colour genes, namely MC1R, and discovered that this particular animal was heterozygous at this locus: one allele encodes what could be a functional peptide, but the other allele encodes a peptide that would have greatly reduced activity. Consequently, the authors were able to conclude that woolly mammoths were very likely to exhibit polymorphism for coat colour!

Sironen, A., Thomsen, B., Andersson, M., Ahola, V., Vilkki, J. :

An intronic insertion in KPL2 results in aberrant splicing and causes the immotile short-tail sperm defect in the pig. Proc Natl Acad Sci U S A 103:5006-11, 2006. Pubmed reference: 16549801. DOI: 10.1073/pnas.0506318103.

Why is this an OMIA landmark paper? It is another good example of the power of the comparative positional candidate-gene approach. In this case, the authors build on previous linkage mapping to fine-map the disorder locus in the pig, which they then showed to be homologous with a region of human chromosome HSA5, which harbours a likely candidate gene, namely a hypothetical human gene that closely resembled the rat gene KPL2, which is expressed in the right tissue (testicular seminiferous tubules). Sequencing of affecteds and normals revealed the causative mutation as retrotransposon insertion within an intron.

2007

Karageorgos, L., Hill, B., Bawden, MJ., Hopwood, JJ. :

Bovine mucopolysaccharidosis type IIIB. Journal of Inherited Metabolic Disease 30:358-64, 2007. Pubmed reference: 17458708. DOI: 10.1007/s10545-007-0539-5.

Why is this an OMIA landmark paper? This is another example of the first report of a disorder in a species (in this case, cattle) being combined in a single paper with a description of the likely causal mutation.

Karlsson, E.K., Baranowska, I., Wade, C.M., Salmon Hillbertz, N.H., Zody, M.C., Anderson, N., Biagi, T.M., Patterson, N., Pielberg, G.R., Kulbokas, E.J., Comstock, K.E., Keller, E.T., Mesirov, J.P., von Euler, H., Kämpe, O., Hedhammar, A., Lander, E.S., Andersson, G., Andersson, L., Lindblad-Toh, K. :

Efficient mapping of mendelian traits in dogs through genome-wide association. Nat Genet 39:1321-8, 2007. Pubmed reference: 17906626. DOI: 10.1038/ng.2007.10.

Why is this an OMIA landmark paper? It is the first of two papers (the other being Charlier et al., 2008) that heralded the amazing power and potential of genome-wide SNP maps. With only a “handful” of affected and control animals (10 cases and 10 controls), the authors showed that it is possible to fine-map Mendelian traits using a high-density SNP panel, to such an extent that it becomes relatively simple to choose among the small number of positional candidate genes residing in that small region.

2008

Charlier, C., Coppieters, W., Rollin, F., Desmecht, D., Agerholm, JS., Cambisano, N., Carta, E., Dardano, S., Dive, M., Fasquelle, C., Frennet, JC., Hanset, R., Hubin, X., Jorgensen, C., Karim, L., Kent, M., Harvey, K., Pearce, BR., Simon, P., Tama, N., Nie, H., Vandeputte, S., Lien, S., Longeri, M., Fredholm, M., Harvey, RJ., Georges, M. :

Highly effective SNP-based association mapping and management of recessive defects in livestock. Nat Genet 40:449-54, 2008. Pubmed reference: 18344998. DOI: 10.1038/ng.96.

Why is this an OMIA landmark paper? This is the second of two papers (the other being Karlsson et al., 2007) that heralded the amazing power and potential of genome-wide SNP maps. With only a “handful” of affected and control animals (3–12 cases and 9–24 controls in this case), the authors showed that it is possible to fine-map Mendelian traits using a high-density SNP panel, to such an extent that it becomes relatively simple to choose among the small number of positional candidate genes residing in that small region.

Eriksson, J., Larson, G., Gunnarsson, U., Bed'hom, B., Tixier-Boichard, M., Stromstedt, L., Wright, D., Jungerius, A., Vereijken, A., Randi, E., Jensen, P, Andersson, L. :

Identification of the yellow skin gene reveals a hybrid origin of the domestic chicken. PLoS Genetics 4:(2):e1000010, 2008. Pubmed reference: 18454198. DOI: 10.1371/journal.pgen.1000010.

Why is this an OMIA landmark paper? This was the first paper that identified BCO2 as a key gene for controlling variation in carotenoid-based pigmentation in vertebrates and has been followed by a number of studies revealing the role of BCO2 for variation in skin, tissue and feather pigmentation. In addition to reporting the causal mutation for one of the original six animal traits reported to be Mendelian (see Bateson [1902] and Bateson and Saunders [1902] among this list of OMIA landmark papers), this paper also shows that present-day poultry evolved not only from the red jungle fowl (as Darwin had correctly surmised), but also derive from the grey jungle fowl, which was the source of the yellow-skin allele.

Norris, BJ., Whan, VA. :

A gene duplication affecting expression of the ovine ASIP gene is responsible for white and black sheep. Genome Res 18:1282-93, 2008. Pubmed reference: 18493018. DOI: 10.1101/gr.072090.107.

Why is this an OMIA landmark paper? After many years of research into the iconic white fleece phenotype in sheep, these authors uncovered a most complex mutation, namely a 190kb tandem duplication encompassing the ASIP gene, the neighbouring AHCY gene and the promoter for a third gene ITCH. This duplicated promoter is so placed as to cause ubiquitous expression of the ASIP gene immediately downstream from it, resulting in the white phenotype. Black sheep are homozygous for a single copy of ASIP with a non-functional promoter. This was the first report of a duplication giving rise to an inherited trait in sheep.

Rosengren Pielberg, G., Golovko, A., Sundstrom, E., Curik, I., Lennartsson, J., Seltenhammer, M.H., Druml, T., Binns, M., Fitzsimmons, C., Lindgren, G., Sandberg, K., Baumung, R., Vetterlein, M., Stromberg, S., Grabherr, M., Wade, C., Lindblad-Toh, K., Ponten, F., Heldin, C-H., Solkner, J., Andersson, L. :

A cis-acting regulatory mutation causes premature hair graying and susceptibility to melanoma in the horse Nature Genetics 40:1004-1009, 2008. Pubmed reference: 18641652. DOI: 10.1038/ng.185.

Why is this an OMIA landmark paper? It reports the causal mechanism for a classic horse phenotype, namely greying with age. These authors presented convincing evidence that this phenotype is due to a 4.6kb intronic duplication in the gene for syntaxin-17 (STX17). This duplication appears to increase the expression of both syntaxin-17 and a neighbouring gene NR4A3, which encodes nuclear receptor subfamily 4, group A, member 3.

Zeng, BJ., Torres, PA., Viner, TC., Wang, ZH., Raghavan, SS., Alroy, J., Pastores, GM., Kolodny, EH. :

Spontaneous appearance of Tay-Sachs disease in an animal model. Mol Genet Metab 95:59-65, 2008. Pubmed reference: 18693054. DOI: 10.1016/j.ymgme.2008.06.010.

Why is this an OMIA landmark paper? In a clear sign of the times, in a single paper Zeng et al. (2008) not only described the occurrence of a lysosomal storage disease in just two American flamingoes, but also, based on the clinical signs and pathology of these two birds, were able to show the cause as a P469L missense mutation in exon 12 of the HEXA gene. Although the disorder had been reported in other species of non-laboratory animals, this was the first reported case of naturally-occurring HEXA deficiency in animals to be characterised at the DNA level.

2010

Drögemüller, C., Tetens, J., Sigurdsson, S., Gentile, A., Testoni, S., Lindblad-Toh, K., Leeb, T. :

Identification of the bovine Arachnomelia mutation by massively parallel sequencing implicates sulfite oxidase (SUOX) in bone development. PLoS Genet 6(8):e1001079, 2010. Pubmed reference: 20865119. DOI: 10.1371/journal.pgen.1001079.

Why is this an OMIA landmark paper? This paper appears to be the first in which a causative mutation was discovered in non-laboratory animals by the use of sequence capture of only the targeted region of the genome, followed by massively parallel (next-generation) (re-)sequencing. The targeted region had been identified by linkage analysis. Only two animals were required for sequencing: one homozygous for the mutated allele, and the other heterozygous.

Flisikowski, K., Venhoranta, H., Nowacka-Woszuk, J., McKay, SD., Flyckt, A., Taponen, J., Schnabel, R., Schwarzenbacher, H., Szczerbal, I., Lohi, H., Fries, R., Taylor, JF., Switonski, M., Andersson, M. :

A novel mutation in the maternally imprinted PEG3 domain results in a loss of MIMT1 expression and causes abortions and stillbirths in cattle (Bos taurus). PLoS One 5:e15116, 2010. Pubmed reference: 21152099. DOI: 10.1371/journal.pone.0015116.

Why is this an OMIA landmark paper? It represents an excellent example of informed detective work leading to the discovery of a most unusual biological phenomenon. A Finnish Ayrshire bull used widely in artificial insemination had an incidence of almost 50% of late abortion/stillbirth in his progeny. A half-sib linkage analysis of 5 dead and 13 live offspring of the bull, with the BovineSNP50 BeadChip (15,631 SNPs), implicated the maternally imprinted PEG3 domain on chromosome BTA18. Genes in this region are not expressed when inherited from the female parent. Close examination of this region disclosed that this bull was heterozygous for a 110 kb deletion in the MIMT1 gene. All of his offspring will have received a non-functional (maternally imprinted) version of this gene from their dam. The 50% of his offspring that receive the deletion from the bull will therefore have no functional MIMT1 gene. The vast majority of these offspring die in late pregnancy, resulting in late abortion/stillbirth.

2011

Buitkamp, J., Semmer, J., Götz, K.U. :

Arachnomelia syndrome in Simmental cattle is caused by a homozygous 2-bp deletion in the molybdenum cofactor synthesis step 1 gene (MOCS1). BMC Genet 12:11, 2011. Pubmed reference: 21255426. DOI: 10.1186/1471-2156-12-11.

Why is this an OMIA Landmark paper? Because it provides the first known example of mutations in two genes involved in the same biochemical pathway giving rise to the same biochemical deficiency and hence the same clinical signs. This paper reports that Arachnomelia in Simmental cattle (OMIA 001541-9913) is due to a 2-bp deletion in the MOCS1 gene (on chromosome BTA23). This gene encodes two peptides (MOCS1A and MOCS1B) via consecutive open reading frames. These two peptides are involved in the synthesis of molybdenum cofactor (Moco), which is involved in the synthesis of sulphite oxidase, the gene for which (SUOX; located on chromosome BTA5) is the site of the mutation for the same disorder in Brown Swiss cattle (Drögemüller et al., 2010) (see OMIA 000059-9913).

García-Gámez, E., Reverter, A., Whan, V., McWilliam, S.M., Arranz, J.J., Kijas, J. :

Using regulatory and epistatic networks to extend the findings of a genome scan: identifying the gene drivers of pigmentation in merino sheep. PLoS One 6:e21158, 2011. Pubmed reference: 21701676. DOI: 10.1371/journal.pone.0021158.

Why is this an OMIA landmark paper? This is a very early and excellent example of combining the power of SNP-based genome-wide association analysis and network analysis of gene expression data. The authors were able to show clearly the multifactorial nature of inheritance of this trait, and were able to identify several genes showing relevant differential expression that are located in the regions of highly-associated SNPs.

VanRaden, P.M., Olson, K.M., Null, D.J., Hutchison, J.L. :

Harmful recessive effects on fertility detected by absence of homozygous haplotypes. J Dairy Sci 94:6153-61, 2011. Pubmed reference: 22118103. DOI: 10.3168/jds.2011-4624.

Why is this an OMIA Landmark paper? It heralded a new approach to identifying lethal mutants, namely searching for haplotypes that occur at a reasonable frequency in a population but are never homozygous. By harnessing the power of SNP chips, this strategy is a powerful means of identifying lethal alleles that contribute to reproductive failure: this particular paper reported the analysis of BovineSNP50 BeadChip genotyping data of 58,453 Holstein, 5,288 Jersey and 1,991 Brown Swiss cattle in the North American database, confirming 8 known autosomal recessive lethal defects and identifying five new lethals significantly affecting conception rate (3 in Holsteins, and 1 each in Jersey and Brown Swiss). Following a convention proposed by breed-association staff, VanRaden et al. (2011) named the new lethals as HH1, HH2, HH3, JH1 and BH1, where the first letter indicates breed and the second is an abbreviation for haplotype. As the authors noted, this strategy has the distinct advantage of being able to detect recessive lethals without requiring reports from breeders of affected offspring, nor does it require any embryos to be genotyped.

2012

Andersson, L.S., Larhammar, M., Memic, F., Wootz, H., Schwochow, D., Rubin, C.J., Patra, K., Arnason, T., Wellbring, L., Hjälm, G., Imsland, F., Petersen, J.L., McCue, M.E., Mickelson, J.R., Cothran, G., Ahituv, N., Roepstorff, L., Mikko, S., Vallstedt, A., Lindgren, G., Andersson, L., Kullander, K. :

Mutations in DMRT3 affect locomotion in horses and spinal circuit function in mice. Nature 488:642-6, 2012. Pubmed reference: 22932389. DOI: 10.1038/nature11399.

Why is the an OMIA landmark paper? It shows the power of genome-wide association studies (GWAS) followed by resequencing within that region, to pinpoint first a chromosomal region and then a mutation in a gene within that region, that plays a major role in determining modes of locomotion in mammals.

Carlson, D.F., Tan, W., Lillico, S.G., Stverakova, D., Proudfoot, C., Christian, M., Voytas, D.F., Long, C.R., Whitelaw, C.B., Fahrenkrug, S.C. :

Efficient TALEN-mediated gene knockout in livestock. Proc Natl Acad Sci U S A 109:17382-7, 2012. Pubmed reference: 23027955. DOI: 10.1073/pnas.1211446109.

Why is this an OMIA landmark paper? It is the first report in non-laboratory animals of the use of Transcription Activator-Like Effector Nucleases (TALENs) to create cloned animals containing specific pre-planned gene mutations. The use of TALENs holds much promise for the investigation of the role of genes by the creation of animals with very specific mutations.

Durkin, K., Coppieters, W., Drögemüller, C., Ahariz, N., Cambisano, N., Druet, T., Fasquelle, C., Haile, A., Horin, P., Huang, L., Kamatani, Y., Karim, L., Lathrop, M., Moser, S., Oldenbroek, K., Rieder, S., Sartelet, A., Sölkner, J., Stålhammar, H., Zelenika, D., Zhang, Z., Leeb, T., Georges, M., Charlier, C. :

Serial translocation by means of circular intermediates underlies colour sidedness in cattle. Nature 482:81-4, 2012. Pubmed reference: 22297974. DOI: 10.1038/nature10757.

Why is this an OMIA landmark paper? It reports a novel and most interesting genetic phenomenon associated with the dorsal white stripe in cattle (called "colour-sided"), which maps to chromosome BTA29. This phenotype is due to the insertion of a duplicated 480kb fragment of DNA from BTA6 that includes the KIT gene but not all its regulators. The stripe appears to result from the at-least-partially unregulated expression of the translocated KIT. Interestingly, the gene order in the translocated segment on BTA29 is different from the gene order on BTA6, consistent with the duplicated region forming a loop which broke at a different location before being inserted in BTA29. Copies of the translocated fragment had escaped from BTA29, formed loops, and then were inserted alongside the original fragment on BTA6.

Forman, O.P., De Risio, L., Stewart, J., Mellersh, C.S., Beltran, E. :

Genome-wide mRNA sequencing of a single canine cerebellar cortical degeneration case leads to the identification of a disease associated SPTBN2 mutation. BMC Genet 13:55, 2012. Pubmed reference: 22781464. DOI: 10.1186/1471-2156-13-55.

Why is this an OMIA landmark paper? It is the first example in domestic animals of the identification of a causal mutation by genome-wide sequencing of RNA (mRNA-Seq) from the relevant tissue of just a single affected animal. In this case the tissue was cerebellum. The canine sequence data were compared with sequence of 27 human genes in which mutations have caused similar clinical signs in humans, and which have canine homologues. One of the canine homologues, SPTBN2, turned out to have an 8bp deletion which segregates perfectly with the canine disease.

Grall, A., Guaguère, E., Planchais, S., Grond, S., Bourrat, E., Hausser, I., Hitte, C., Le Gallo, M., Derbois, C., Kim, G.J., Lagoutte, L., Degorce-Rubiales, F., Radner, F.P., Thomas, A., Küry, S., Bensignor, E., Fontaine, J., Pin, D., Zimmermann, R., Zechner, R., Lathrop, M., Galibert, F., André, C., Fischer, J. :

PNPLA1 mutations cause autosomal recessive congenital ichthyosis in golden retriever dogs and humans. Nat Genet 44:140-7, 2012. Pubmed reference: 22246504. DOI: 10.1038/ng.1056.

Why is this an OMIA landmark paper? It shows how a discovery in animals can lead to important discoveries concerning humans. Having identified the causal mutation of this disorder in dogs, as being an insertion-deletion mutation in the PNPLA1 gene, the authors then showed that some cases of the homologous disorder in humans are due to mutations in the human PNPLA1 gene, this being a gene not previously implicated in human disorders.

Imsland, F., Feng, C., Boije, H., Bed'hom, B., Fillon, V., Dorshorst, B., Rubin, C-J., Liu, R., Gao, Y., Gu, X., Wang, Y., Gourichon, D., Zody, M.C., Zecchin, W., Vieaud, A., Tixier-Boichard, M., Hu, X., Hallböök, F., Li, N., Andersson, L. :

The rose-comb mutation in chickens constitutes a structural rearrangement causing both altered comb morphology and defective sperm motility. PLoS Genetics 8(6):e1002775, 2012. Pubmed reference: 22761584. DOI: 10.1371/journal.pgen.1002775.

Why is this an OMIA landmark paper? Besides providing the molecular basis of one of the first six animal Mendelian traits to be described (by Bateson, 1902, and Bateson and Saunders, 1902), this paper also includes a molecular explanation for the very first case of epistasis (interaction between genes) ever reported (by Bateson et al., 1905; see earlier paper in this Landmark section), namely the interaction between the Rose-comb and Pea-comb loci, resulting in Walnut-comb. Finally, the paper also provides an explanation for the well-documented pleiotropic effect of Rose-comb, namely that male homozygotes have poor sperm motility, which is likely to arise from the inversion breakpoint of allele R1 coinciding with a gene (CCDC108) whose encoded peptide includes a major sperm protein domain.

Kaelin, C.B., Xu, X., Hong, L.Z., David, V.A., McGowan, K.A., Schmidt-Küntzel, A., Roelke, M.E., Pino, J., Pontius, J., Cooper, G.M., Manuel, H., Swanson, W.F., Marker, L., Harper, C.K., van Dyk, A., Yue, B., Mullikin, J.C., Warren, W.C., Eizirik, E., Kos, L., O'Brien, S.J., Barsh, G.S., Menotti-Raymond, M. :

Specifying and sustaining pigmentation patterns in domestic and wild cats. Science 337:1536-41, 2012. Pubmed reference: 22997338. DOI: 10.1126/science.1220893.

Why is this an OMIA Landmark paper? It describes the discovery of the molecular basis of the classic feline tabby coat-colour pattern, and proposes a biochemical model for the phenotype. It also shows that a mutation in the orthologous gene in cheetahs is responsible for the king coat colour pattern in that species.

Medugorac, I., Seichter, D., Graf, A., Russ, I., Blum, H., Göpel, K.H., Rothammer, S., Förster, M., Krebs, S. :

Bovine polledness - an autosomal dominant trait with allelic heterogeneity. PLoS One 7:e39477, 2012. Pubmed reference: 22737241. DOI: 10.1371/journal.pone.0039477.

Why is this an OMIA landmark paper? One hundred and ten years after bovine polledness was one of the first six animal traits described as being Mendelian (by Bateson and Saunders, 1902; also an OMIA landmark paper), this paper reports two polled alleles in cattle of European origin, one in cattle of "Celtic" origin and one in cattle of Friesian origin, each of which is a complex indel. The fact that these alleles are located in a region in which there is no known coding, regulatory or any other type of "functional" DNA shows that we are still a long way from having a complete understanding of this locus.

Wells, K.L., Hadad, Y., Ben-Avraham, D., Hillel, J., Cahaner, A., Headon, D.J. :

Genome-wide SNP scan of pooled DNA reveals nonsense mutation in FGF20 in the Scaleless line of featherless chickens. BMC Genomics 13:257, 2012. Pubmed reference: 22712610. DOI: 10.1186/1471-2164-13-257.

Why is this an OMIA landmark paper? It reports the first non-human example of mapping a single-locus trait (in this case, an autosomal recessive trait) by SNP-chip-genotyping a DNA pool of homozygote recessives and another DNA pool of heterozygotes. In other words, the trait was mapped by the use of only two SNP-chips. This two-pool strategy was rendered effective by the two pools having been created from a test-cross (sc/sc males X +/sc females). This is important as it ensured that the two groups shared the same average genetic background, and differed only in the region linked to the segregating Mendelian gene. (Thanks to Avigdor Cahaner for providing the essence of the last two sentences).

2013

Buckingham, K.J., McMillin, M.J., Brassil, M.M., Shively, K.M., Magnaye, K.M., Cortes, A., Weinmann, A.S., Lyons, L.A., Bamshad, M.J. :

Multiple mutant T alleles cause haploinsufficiency of Brachyury and short tails in Manx cats. Mamm Genome 24:400-8, 2013. Pubmed reference: 23949773. DOI: 10.1007/s00335-013-9471-1.

Why is this an OMIA Landmark paper? It reports causal mutations for the characteristic short-tail/taillessness trait of Manx cats. This trait was mentioned by Darwin, and, after the rediscovery of Mendelism in 1900, it was the first feline trait to be recognised as Mendelian (listed in Bateson's (1909) "Mendel’s Principles of Heredity").

Johnston, S.E., Gratten, J., Berenos, C., Pilkington, J.G., Clutton-Brock, T.H., Pemberton, J.M., Slate, J. :

Life history trade-offs at a single locus maintain sexually selected genetic variation. Nature 502:93-95, 2013. Pubmed reference: 23965625. DOI: 10.1038/nature12489.

Why is this an OMIA Landmark paper? It describes what will become a classic textbook example of heterozygote advantage (overdominance) for fitness. At the polled/horn locus (encoded by the RXFP2 gene) in Soay sheep, the wild-type horned (Ho+) allele confers higher reproductive success, but the polled/scurred allele (HoP) confers increased survival. The result of this interplay between sexual selection (for large horns) and natural selection (for polled/scurs) leads to heterozygote advantage for fitness, and hence the maintenance of polymorphism at this locus.

2015

Dorshorst, B., Harun-Or-Rashid, M., Bagherpoor, A.J., Rubin, C.J., Ashwell, C., Gourichon, D., Tixier-Boichard, M., Hallböök, F., Andersson, L. :

A genomic duplication is associated with ectopic eomesodermin expression in the embryonic chicken comb and two duplex-comb phenotypes. PLoS Genet 11:e1004947, 2015. Pubmed reference: 25789773. DOI: 10.1371/journal.pgen.1004947.

Why is this an OMIA Landmark paper? Because it completes the discovery of the molecular basis of the "trio" of classic comb types in chickens, namely Pea comb (OMIA 000782-9031), Rose comb (OMIA 000884-9031) and Duplex comb (OMIA 000296-9031). As summarised by the authors, "These findings complete our characterization of the genetic basis of the three major comb loci in the chicken, all of which are caused by large-scale structural genomic variants that drive ectopic expression of transcription factors in the comb region during chicken embryo development".

Lamichhaney, S., Berglund, J., Almén, M.S., Maqbool, K., Grabherr, M., Martinez-Barrio, A., Promerová, M., Rubin, C.J., Wang, C., Zamani, N., Grant, B.R., Grant, P.R., Webster, M.T., Andersson, L. :

Evolution of Darwin's finches and their beaks revealed by genome sequencing. Nature 518:371-5, 2015. Pubmed reference: 25686609. DOI: 10.1038/nature14181.

Why is this an OMIA landmark paper? It shows the incredible power of being able to contrast whole-genome sequence between groups of closely-related animals differing in a trait of importance; and it does this in in relation to one of the standard text-book traits concerning evolution, namely beak shape in Darwin's Galapagos finches. The genome-sequence comparison shows that beak shape is a polygenic trait, and enabled the authors to identify one of these polygenes, i.e. a QTL for beak shape.

2016

Carlson, D.F., Lancto, C.A., Zang, B., Kim, E.S., Walton, M., Oldeschulte, D., Seabury, C., Sonstegard, T.S., Fahrenkrug, S.C. :

Production of hornless dairy cattle from genome-edited cell lines. Nat Biotechnol 34:479-81, 2016. Pubmed reference: 27153274. DOI: 10.1038/nbt.3560.

Why is this an OMIA landmark paper? It reports the successful use of genome editing technology (in this case transcription activator-like effector nucleases; TALENs) to introduce the highly-desirable Celtic polled allele into horned cattle without the need for generations of backcrossing. Just as important is the demonstration that the somewhat mysterious Celtic polled allele, "a sequence variant duplication of unknown function in a genomic region with no known or predicted coding or noncoding genes", is actually causative for polled.

Charlier, C., Li, W., Harland, C., Littlejohn, M., Coppieters, W., Creagh, F., Davis, S., Druet, T., Faux, P., Guillaume, F., Karim, L., Keehan, M., Kadri, N.K., Tamma, N., Spelman, R., Georges, M. :

NGS-based reverse genetic screen for common embryonic lethal mutations compromising fertility in livestock. Genome Res 26:1333-1341, 2016. Pubmed reference: 27646536. DOI: 10.1101/gr.207076.116.

Why is this an OMIA Landmark paper? For a start, its nine new embryonic lethals are the largest number of genes with new causal variants yet published in a single paper. Also, it is an excellent example of the power of reverse genetics via the screening of whole-exome and whole-genome data from large numbers of animals (in this case, more than 600).

Donner, J., Kaukonen, M., Anderson, H., Möller, F., Kyöstilä, K., Sankari, S., Hytönen, M., Giger, U., Lohi, H. :

Genetic panel screening of nearly 100 mutations reveals new insights into the breed distribution of risk variants for canine hereditary disorders. PLoS One 11:e0161005, 2016. Pubmed reference: 27525650. DOI: 10.1371/journal.pone.0161005.

Why is this an OMIA Landmark paper? It is "the first large scale report of DNA panel screening across purebred dogs to date", involving the genotyping of 6,788 dogs from 233 breeds for 93 disease-implicated variants across 80 single-locus disorders, providing a very informative "snapshot" of the distribution and frequency of these variants. Importantly, the results indicated "15 risk variants in a total of 34 breeds in which their presence was previously undocumented", which will be very helpful in the provision of genetic counselling in those breeds. The detection of some of these latter variants led to "plausible molecular explanations" for disorders in some breeds.

Imsland, F., McGowan, K., Rubin, C.J., Henegar, C., Sundström, E., Berglund, J., Schwochow, D., Gustafson, U., Imsland, P., Lindblad-Toh, K., Lindgren, G., Mikko, S., Millon, L., Wade, C., Schubert, M., Orlando, L., Penedo, M.C., Barsh, G.S., Andersson, L. :

Regulatory mutations in TBX3 disrupt asymmetric hair pigmentation that underlies Dun camouflage color in horses. Nat Genet 48:152-8, 2016. Pubmed reference: 26691985. DOI: 10.1038/ng.3475.

Why is this an OMIA Landmark paper? It illustrates the power of genomic analysis to greatly expand our knowledge of T-box transcription-factor genes that are central to embryonic development, in the context of a trait that was of great interest to Charles Darwin (Origin of Species, chap 5, pp. 163-167).

Lamichhaney, S., Han, F., Berglund, J., Wang, C., Almén, M.S., Webster, M.T., Grant, B.R., Grant, P.R., Andersson, L. :

A beak size locus in Darwin's finches facilitated character displacement during a drought. Science 352:470-4, 2016. Pubmed reference: 27102486. DOI: 10.1126/science.aad8786.

Why is this an OMIA Landmark paper? It is another illustration of the power of genomic analysis to throw light on the underlying biology of evolution in the famous so-called Darwin finches of the Galapagos Islands. In this case, the authors have identified a polymorphism that has played a major role in trait divergence - one of Darwin's major evolutionary phenomena.

Lyons, L.A., Creighton, E.K., Alhaddad, H., Beale, H.C., Grahn, R.A., Rah, H., Maggs, D.J., Helps, C.R., Gandolfi, B. :

Whole genome sequencing in cats, identifies new models for blindness in AIPL1 and somite segmentation in HES7. BMC Genomics 17:265, 2016. Pubmed reference: 27030474. DOI: 10.1186/s12864-016-2595-4.

Why is this an OMIA Landmark paper? It is the first case in cats of whole-genome sequencing WGS of a family trio (sire dam and offspring) as a means of identifying likely causal variants, in this case, the trio was segregating for Leber’s congenital amaurosis and bobtail, thereby enabling the likely causal mutation for each disorder to be readily identified. This paper was published just two months after the first report of WGS of a family trio in any OMIA species (Sayyab et al., 2016; below).

Michot, P., Chahory, S., Marete, A., Grohs, C., Dagios, D., Donzel, E., Aboukadiri, A., Deloche, M.C., Allais-Bonnet, A., Chambrial, M., Barbey, S., Genestout, L., Boussaha, M., Danchin-Burge, C., Fritz, S., Boichard, D., Capitan, A. :

A reverse genetic approach identifies an ancestral frameshift mutation in RP1 causing recessive progressive retinal degeneration in European cattle breeds. Genet Sel Evol 48:56, 2016. Pubmed reference: 27510606. DOI: 10.1186/s12711-016-0232-y.

Why is this an OMIA Landmark paper? It is an excellent large-scale illustration of the power of genomic sequence analysis to identify potentially harmful variants (genetic load). Interestingly, the evidence from this study is that most of the potentially harmful variants have existed longer than most breeds.

Sayyab, S., Viluma, A., Bergvall, K., Brunberg, E., Jagannathan, V., Leeb, T., Andersson, G., Bergström, T.F. :

Whole-genome sequencing of a canine Family trio Reveals a FAM83G variant associated with hereditary footpad hyperkeratosis. G3 (Bethesda) 6:521-527, 2016. Pubmed reference: 26747202. DOI: 10.1534/g3.115.025643.

Why is this an OMIA Landmark paper? It is the first report in an OMIA species of the use of whole-genome sequencing of a family trio (sire, dam and offspring) to identify a likely causal variant. In this case, the variant identification was actually a confirmation of a previously-discovered likely causal variant. [FN thanks Hamutal Mazrier for bringing this discovery to his attention]

2017

Bourneuf, E., Otz, P., Pausch, H., Jagannathan, V., Michot, P., Grohs, C., Piton, G., Ammermüller, S., Deloche, M.C., Fritz, S., Leclerc, H., Péchoux, C., Boukadiri, A., Hozé, C., Saintilan, R., Créchet, F., Mosca, M., Segelke, D., Guillaume, F., Bouet, S., Baur, A., Vasilescu, A., Genestout, L., Thomas, A., Allais-Bonnet, A., Rocha, D., Colle, M.A., Klopp, C., Esquerré, D., Wurmser, C., Flisikowski, K., Schwarzenbacher, H., Burgstaller, J., Brügmann, M., Dietschi, E., Rudolph, N., Freick, M., Barbey, S., Fayolle, G., Danchin-Burge, C., Schibler, L., Bed'Hom, B., Hayes, B.J., Daetwyler, H.D., Fries, R., Boichard, D., Pin, D., Drögemüller, C., Capitan, A. :

Rapid discovery of de novo deleterious mutations in cattle enhances the value of livestock as model species. Sci Rep 7:11466, 2017. Pubmed reference: 28904385. DOI: 10.1038/s41598-017-11523-3.

Why is this an OMIA Landmark paper? The authors show that exploiting "the availability of large data sets of whole-genome sequences, high-density SNP chip genotypes and extensive recording of phenotype" in the context of the large sire families typical of cattle "offers an unprecedented opportunity to quickly dissect the genetic architecture of severe dominant conditions in livestock." For each of seven dominant disorders, the strategy involved whole-genome sequencing of just one affected animal, calling variants and filtering them "to retain heterozygous polymorphisms that were absent from 1230 control genomes . . . and were predicted to be deleterious to protein function . . . For each of the seven conditions studied, the large number of control genomes enabled [the authors] to decrease the number of candidate causal polymorphisms from millions to only one mutation", each of which was shown to be de novo. The authors also showed how "Large half-sib pedigrees allow for the mapping of modifier loci in clinically variable syndromes." Importantly, the authors also showed how "the detection of de novo deleterious [recessive] mutations in [the] genomes [of young elite bulls] will enable the management of recessive defects in livestock populations before a large number of affected calves emerge." The authors illustrated the power of this strategy by identifying seven de novo recessive variants in 43 young elite French bulls. As proof of concept, one of these variants was shown to be likely causal for a recessive skin disorder. Equally importantly, since each of the studied disorders is a model for a human disorder, the strategies illustrated in this paper offer much promise for the rapid discovery of new animal models for human disorders.

Gurda, B.L., Bradbury, A.M., Vite, C.H. :

Canine and Feline Models of Human Genetic Diseases and Their Contributions to Advancing Clinical Therapies . Yale J Biol Med 90:417-431, 2017. Pubmed reference: 28955181.

Why is this an OMIA Landmark paper? Because it highlights the enormous contribution made by "Dr. Donald F. Patterson and continued by Dr. Mark E. Haskins at the University of Pennsylvania with the mission to discover, understand, treat, and maintain breeding colonies of naturally occurring hereditary disorders in dogs and cats that are orthologous to those found in human patients."

Medugorac, I., Graf, A., Grohs, C., Rothammer, S., Zagdsuren, Y., Gladyr, E., Zinovieva, N., Barbieri, J., Seichter, D., Russ, I., Eggen, A., Hellenthal, G., Brem, G., Blum, H., Krebs, S., Capitan, A. :

Whole-genome analysis of introgressive hybridization and characterization of the bovine legacy of Mongolian yaks. Nat Genet 49:470-475, 2017. Pubmed reference: 28135247. DOI: 10.1038/ng.3775.

Why is this an OMIA Landmark paper? It reports the use of very powerful genomic tools to show that the herding together of Mongolian Turano cattle and domestic yaks has resulted in Mongolian yaks inheriting "on average 1.31% of their genome from bovine ancestors after nearly continuous admixture over at least the last 1,500 years and . . . that introgressed segments are significantly enriched in genes involved in nervous system development and function, which probably have contributed to the taming of yaks. We also show introgression of a new mutation that determines a phenotype of primary interest in bovine and yak husbandry: the genetic absence of horns"; and also the introgression of colour-sidedness (OMIA 001576-30521).

Utsunomiya, Y.T., Milanesi, M., Utsunomiya, A.T.H., Torrecilha, R.B.P., Kim, E.S., Costa, M.S., Aguiar, T.S., Schroeder, S., do Carmo, A.S., Carvalheiro, R., Neves, H.H.R., Padula, R.C.M., Sussai, T.S., Zavarez, L.B., Cipriano, R.S., Caminhas, M.M.T., Hambrecht, G., Colli, L., Eufemi, E., Ajmone-Marsan, P., Cesana, D., Sannazaro, M., Buora, M., Morgante, M., Liu, G., Bickhart, D., Van Tassell, C.P., Sölkner, J., Sonstegard, T.S., Garcia, J.F. :

A PLAG1 mutation contributed to stature recovery in modern cattle. Sci Rep 7:17140, 2017. Pubmed reference: 29215042. DOI: 10.1038/s41598-017-17127-1.

Utsunomiya et al. (2017): "this study presents one of the first examples of a selective sweep in livestock that was driven by strong (supposedly artificial) selection on a complex trait."

2019

Cai, S.V., Famula, T.R., Oberbauer, A.M., Hess, R.S. :

Heritability and complex segregation analysis of diabetes mellitus in American Eskimo Dogs. J Vet Intern Med 33:1926-1934, 2019. Pubmed reference: 31318104. DOI: 10.1111/jvim.15570.

Why is this an OMIA Landmark paper? Because it provides a textbook example of how to estimate the heritability of a disorder, and to investigate its mode of inheritance. The authors used logistical regression to estimate heritability, and complex segregation analysis to investigate the mode of inheritance.

Hill, J., Enbody, E.D., Pettersson, M.E., Sprehn, C.G., Bekkevold, D., Folkvord, A., Laikre, L., Kleinau, G., Scheerer, P., Andersson, L. :

Recurrent convergent evolution at amino acid residue 261 in fish rhodopsin. Proc Natl Acad Sci U S A 116:18473-18478, 2019. Pubmed reference: 31451650. DOI: 10.1073/pnas.1908332116.

Why is this an OMIA Landmark paper? It reports a remarkable example of convergent evolution at the level of a single amino-acid.

2020

Bortoluzzi, C., Megens, H.J., Bosse, M., Derks, M.F.L., Dibbits, B., Laport, K., Weigend, S., Groenen, M.A.M., Crooijmans, R.P.M.A. :

Parallel genetic origin of foot feathering in birds. Mol Biol Evol 37:2465-2476, 2020. Pubmed reference: 32344429. DOI: 10.1093/molbev/msaa092.

Why is this an OMIA Landmark paper? In adjacent papers published in the same issue of Molecular Biology and Evolution, Bortoluzzi et al. (2020) and Li et al. (2020) presented an intriguing example of parallel/convergent evolution of the feathered shank trait (ptilopody) in chickens and pigeons. In both species, the trait is determined by mutations relating to orthologous genes, namely TBX5 (chickens) and Tbx5 (pigeons), and PITX1 (chickens) and Pitx1 (pigeons). In the case of PITX1 and Pitx1, respectively, the mutations are a 17.7kb upstream deletion (chickens) and a 44kb upstream deletion (pigeons), with the former being located within the orthologous region of the latter.

Buckley, R.M., Grahn, R.A., Gandolfi, B., Herrick, J.R., Kittleson, M.D., Bateman, H.L., Newsom, J., Swanson, W.F., Prieur, D.J., Lyons, L.A. :

Assisted reproduction mediated resurrection of a feline model for Chediak-Higashi syndrome caused by a large duplication in LYST. Sci Rep 10:64, 2020. Pubmed reference: 31919397. DOI: 10.1038/s41598-019-56896-9.

Why is this an OMIA Landmark paper? Because it shows how a likely causal variant can be discovered in a cell line from a long-dead animal, and then can be tested by genotyping a family of cats created by the use of cryo-preserved semen from a long-since discarded research colony in which the variant (and hence the disorder) had been segregating.

Li, J., Lee, M., Davis, B.W., Lamichhaney, S., Dorshorst, B.J., Siegel, P.B., Andersson, L. :

Mutations upstream of the TBX5 and PITX1 transcription factor genes are associated with feathered legs in the domestic chicken. Mol Biol Evol 37:2477-2486, 2020. Pubmed reference: 32344431. DOI: 10.1093/molbev/msaa093.

Mui, M.L., Famula, T.R., Henthorn, P.S., Hess, R.S. :

Heritability and complex segregation analysis of naturally-occurring diabetes in Australian Terrier Dogs. PLoS One 15:e0239542, 2020. Pubmed reference: 32970763. DOI: 10.1371/journal.pone.0239542.

Why is this an OMIA Landmark paper? Because it provides a second textbook example of how to estimate the heritability of a disorder, and to investigate its mode of inheritance (the first being by Cai et al., 2019; see Landmark papers for 2019). As in the paper by Cai et al. (2019), the authors used logistical regression to estimate heritability, and complex segregation analysis to investigate the mode of inheritance.

2021

Allais-Bonnet, A., Hintermann, A., Deloche, M.C., Cornette, R., Bardou, P., Naval-Sanchez, M., Pinton, A., Haruda, A., Grohs, C., Zakany, J., Bigi, D., Medugorac, I., Putelat, O., Greyvenstein, O., Hadfield, T., Jemaa, S.B., Bunevski, G., Menzi, F., Hirter, N., Paris, J.M., Hedges, J., Palhiere, I., Rupp, R., Lenstra, J.A., Gidney, L., Lesur, J., Schafberg, R., Stache, M., Wandhammer, M.D., Arbogast, R.M., Guintard, C., Blin, A., Boukadiri, A., Rivière, J., Esquerré, D., Donnadieu, C., Danchin-Burge, C., Reich, C.M., Riley, D.G., van Marle-Koster, E., Cockett, N., Hayes, B.J., Drögemüller, C., Kijas, J., Pailhoux, E., Tosser-Klopp, G., Duboule, D., Capitan, A. :

Analysis of polycerate mutants reveals the evolutionary co-option of HOXD1 for horn patterning in bovidae. Mol Biol Evol 38:2260-72, 2021. Pubmed reference: 33528505. DOI: 10.1093/molbev/msab021.

Why is this an OMIA Landmark paper? Because it reports the molecular basis of a classic trait (polyceraty) in both sheep and goats, showing that the likely causal variant in each species is a mutation in the HOXD1 gene; a 4bp deletion in sheep and a 500kb deletion-137kb insertion in goats. The authors conclude that in both species "haploinsufficiency at this locus results in the splitting of horn bud primordia, likely following the abnormal extension of an initial morphogenetic field. These results highlight the key role played by this gene in headgear patterning and illustrate the evolutionary co-option of a gene involved in the early development of bilateria to properly fix the position and number of these distinctive organs of Bovidae".

Enbody, E.D., Sprehn, C.G., Abzhanov, A., Bi, H., Dobreva, M.P., Osborne, O.G., Rubin, C.J., Grant, P.R., Grant, B.R., Andersson, L. :

A multispecies BCO2 beak color polymorphism in the Darwin's finch radiation. Curr Biol 31:5597-5604, 2021. Pubmed reference: 34687609. DOI: 10.1016/j.cub.2021.09.085.

Why is this an OMIA Landmark paper? This paper proposes a synonymous variant as likely casual variant for a beak colour polymorphism and is providing substantial evidence to support this hypothesis.

Reynolds, E.G.M., Neeley, C., Lopdell, T.J., Keehan, M., Dittmer, K., Harland, C.S., Couldrey, C., Johnson, T.J.J., Tiplady, K., Worth, G., Walker, M., Davis, S.R., Sherlock, R.G., Carnie, K., Harris, B.L., Charlier, C., Georges, M., Spelman, R.J., Garrick, D.J., Littlejohn, M.D. :

Non-additive association analysis using proxy phenotypes identifies novel cattle syndromes. Nat Genet 53:949-54, 2021. Pubmed reference: 34045765. DOI: 10.1038/s41588-021-00872-5.

Why is this an OMIA Landmark paper? Reynolds et al. (2021) “report one of the largest sequence-resolution screens of cattle to date, targeting discovery and validation of non-additive effects in 130,725 animals”. … [Their] discoveries demonstrate the use of proxy phenotypes to directly map deleterious effects in the absence of prior disease identification, an approach that holds promise for the identification of similar effects in other selected species.”

2022

Besnard, F., Leclerc, H., Boussaha, M., Grohs, C., Jewell, N., Pinton, A., Barasc, H., Jourdain, J., Femenia, M., Dorso, L., Strugnell, B., Floyd, T., Danchin, C., Guatteo, R., Cassart, D., Hubin, X., Mattalia, S., Boichard, D., Capitan, A. :

Detailed analysis of mortality rates in the female progeny of 1,001 Holstein bulls allows the discovery of new dominant genetic defects. J Dairy Sci 106:439-451, 2022. Pubmed reference: 36333145. DOI: 10.3168/jds.2022-22365.

Why is this an OMIA Landmark paper? Reducing juvenile mortality has become a growing concern in livestock industry not only for economic reasons but also for animal welfare and environmental concerns. The authors used an innovative approach to identify dominant genetic defects that may have been overlooked by traditional surveillance platforms. They analyzed mortality rates in the progeny of artificial insemination sires, assuming that extreme values hide congenital anomalies. As a proof of concept, they investigated the progeny of two outlier sires and described two new dominant syndromes in cattle due to de novo mutations. These results demonstrate the suitability of the approach to reveal genetic defects that are hardly detectable with traditional surveillance in the absence of specific externally visible symptoms. Beyond this proof of concept, the calculation of mortality rates at different ages for the whole population of bulls paves the way for future detection of QTL influencing juvenile mortality.

2023

Boeykens, F., Bhatti, S.F.M., Peelman, L., Broeckx, B.J.G. :

VariantscanR: an R-package as a clinical tool for variant filtering of known phenotype-associated variants in domestic animals. BMC Bioinformatics 24:305, 2023. Pubmed reference: 37528412. DOI: 10.1186/s12859-023-05426-6.

Why is this an OMIA Landmark paper? Boeykens et al. have created an R-package called VariantscanR that uses a table of likely causal variants downloaded from OMIA (or created manually) to interrogate VCF files from “whole genome sequencing (WGS) and whole exome sequencing (WES)” of an individual animal. Among other outputs, the package reports the genotype of the animal at every locus for which a likely causal variant has been reported, thereby facilitating the choice of mating pairs in the control of inherited disorders.

Id-Lahoucine, S., Casellas, J., Miglior, F., Schenkel, F.S., Cánovas, A. :

Parent-offspring genotyped trios unravelling genomic regions with gametic and genotypic epistatic transmission bias on the cattle genome. Front Genet 14:1132796, 2023. Pubmed reference: 37091801. DOI: 10.3389/fgene.2023.1132796.

Why is this an OMIA Landmark paper? Id-Lahoucine et al. (2023) propose an approach to identify pairs of loci with epistatic transmission ratio distortion by analysing parent-offspring genotyped trios in cattle. The authors identified "candidate genomic regions harboring epistatic interactions with potential biological implications in economically important traits, such as reproduction."

Surati, U., M, M., S, J., Verma, A., Niranjan, S.K. :

Genome-wide in silico analysis leads to identification of deleterious L290V mutation in RBBP5 gene in Bos indicus. Anim Biotechnol 34:4851-4859, 2023. Pubmed reference: 37051916. DOI: 10.1080/10495398.2023.2199502.

Why is this an OMIA Landmark paper? Surati et al. (2023) used bioinformatic tools to analyse ddRAD sequence data to predict deleterious DNA mutations in absence of records of genetic disease.

2024

Haque, B., Guirguis, G., Curtis, M., Mohsin, H., Walker, S., Morrow, M.M., Costain, G. :

A comparative medical genomics approach may facilitate the interpretation of rare missense variation. J Med Genet 61:817-821, 2024. Pubmed reference: 38508706. DOI: 10.1136/jmg-2023-109760.

A team of human geneticists in Toronto, Canada, led by Greg Costain, has shown that pathogenic missense variants in OMIA provide useful indications of the likely pathogenicity of comparable human variants (same gene, same peptide residue). The authors conclude: “These results provide further support for comparative medical genomics approaches that connect big data initiatives in human and veterinary genetics.”

The University of Sydney - OMIA - Online Mendelian Inheritance in Animals

Landmark articles