In other species: cattle , sheep , water buffalo , bighorn sheep , kouprey , domestic yak , zebu

Categories: Craniofacial phene

Possibly relevant human trait(s) and/or gene(s) (MIM number): 110100 (trait)

Links to MONDO diseases: No links.

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2001

Cross-species summary: Horns are paired appendages with a bony core that is attached to the skull and a keratin outer sheath. There is substantial variation in the extent of horn growth, making classification difficult. However, in general, the presence or absence of horns can be attributed to the action of two alleles at an autosomal locus. The type of gene action varies considerably between and among species. Absence of horns is called 'polled'. See also entries for 'scurs'.

Species-specific name: Polled Intersex syndrome (PIS)

Species-specific symbol: PIS

Species-specific description: In goats, intersexuality is a recessive trait associated with the dominant allele for the absence of horns (polled). Some XY goats that are homozygous for the polled allele, are sterile. Most XX goats that are homozygous for the polled allele, show signs of intersexuality, ranging from almost normal female to almost male in external appearance and in development of reproductive tracts and organs. Paihoux et al. (1994) showed that three polled goats with ambiguous genitalia had a normal XX karyotype. These authors also showed an absence of Y-chromosome DNA in these animals, thus ruling out Y-X translocation as a cause of the intersexuality. Similar observations on seven intersex goats were made by Vaiman et al. (1997). (Information complied by Helena Axtoll, Uppsala, March 1998)

History: This appears to be the first published example of the application of the goat SNP50 bead chip.

Inheritance: As in other species, polledness in goats is a single-locus autosomal dominant trait. Unlike in other species, the same allele that confers polledness is autosomal recessive for intersexuality (see Summary above). This somewhat unusual situation was first reported by Asdell (1944).

Mapping: A linkage analysis by Vaiman et al. (1997) showed that the locus for polledness/intersex (PIS) is located in the distal region of chromosome 1. (Information compiled by Helena Axtoll, Uppsala, March 1998). The PIS region was narrowed to 1Mb within band 1q43 by Vaiman et al. (1999). Schibler et al. (2000) narrowed this to 100 kb contained within one BAC clone.

Using the goat SNP50 Bead Chip, Kijas et al. (2012) "collected and analysed genotypes from 52 088 SNPs in Boer, Cashmere and Rangeland goats that had both polled and horned individuals." In confirming the location of the polled locus on chromosome CHI1, they confirmed the mapping of this locus to a "769-kb critical interval . . . , confirming the genetic basis [of the polled intersex syndrome] in non-European animals is the same as identified previously in Saanen goats. Interestingly, analysis of the haplotypes carried by a small set of sex-reversed animals, known to be associated with polledness, revealed some animals carried the wild-type chromosome associated with the presence of horns. This suggests a more complex basis for the relationship between polledness and the intersex condition than initially thought".

Molecular basis: Exon-trapping and subsequent sequencing of the BAC clone that spanned the PIS locus enabled Pailhoux et al. (2001) to identify a gene they called PIS-regulated transcript 1 (PISRT1). The then showed that PIS is due to an 11.7 kb deletion of mainly repetitive DNA which affects the transcription of PISRT1 and a neighbouring gene FOXL2. As noted by the authors, "These two genes are located 20 and 200 kb telomeric from the deletion, respectively". Interestingly, a mutation of FOXL2 in humans gives rise to Blepharophimosis Ptosis Epicanthus inversus Syndrome (BPES; see MIM hyperlink above) which is a disorder somewhat similar to PIS.

Further investigations enabled Pailhoux et al. (2005) to conclude that the deletion "is composed for 80% of two copies of a partial ruminant LINE (2.2 and 2.6 kilobases), oriented head to head, 25 kilobases apart from PISRT1." They also reported that "FOXL2 may be an ovary-differentiating gene, and the non-coding RNA PISRT1, an anti-testis factor repressing SOX9, a key regulator of testis differentiation. Under this hypothesis, SRY, the testis-determining factor would inhibit these two genes in the gonads of XY males, to ensure testis differentiation."

Allais-Bonnet et al. (2013) established a link between polledness in goats and cattle when they discovered that a trait strongly associated with polledness in cattle, namely two rows of eyelashes (distichiasis; OMIA 001841-9913), is caused in humans by mutations in FOXC2, which is a paralogue of FOXL2. Subsequent gene expression studies of this gene in tissues from polled and horned cattle led these authors to conclude that in both species "FOXL2 is involved in the negative regulation of horn bud differentiation (perhaps to control the diameter of the horn bud or to prevent horn growth before birth)".

Boulanger et al. (2014) provided strong evidence that "FOXL2 [is] a bona fide female sex-determining gene in the goat", i.e. that loss of function of FOXL2 is a sufficient explanation for PIS.

By applying "long‐read whole‐genome sequencing of two genetically female (XX) goats, a PIS‐affected and a horned control", Simon et al. (2020) revisited the 11.7 kb deletion first documented by Pailhoux et al. (2001). Their results "revealed the presence of a more complex structural variant consisting of a deletion with a total length of 10 159 bp and an inversely inserted approximately 480 kb‐sized duplicated segment of a region located approximately 21 Mb further downstream on chromosome 1 containing two genes, KCNJ15 and ERG." The authors "showed that the variant allele was present in all 334 genotyped polled goats of diverse breeds and that all analyzed 15 PIS‐affected XX goats were homozygous." They also reported that "This complex structural variant designated as PIS was absent in the 480 horned control genomes."

E et al. (2021): "The whole-genome selective sweep of intersex goats from China was performed with whole-genome next-generation sequencing technology for large sample populations and a case-control study on interbreeds. A series of candidate genes related to the goat intersexuality phenotype were found. We further confirmed that a ~0.48 Mb duplicated fragment (including ERG and KCNJ15) downstream of the ~20 Mb PIS region was reversely inserted into the PIS locus in intersex Chinese goats and was consistent with that in European Saanen and Valais black-necked goats. High-throughput chromosome conformation capture (Hi-C) technology was then used to compare the 3D structures of the PIS variant neighborhood in CHI1 between intersex and non-intersex goats. A newly found structure was validated as an intrachromosomal rearrangement. This inserted duplication changed the original spatial structure of goat CHI1 and caused the appearance of several specific loop structures in the adjacent ~20 kb downstream region of FOXL2."

Clinical features: Vaiman et al. (1997) reported that all seven XX intersexes had two inguinally-located udders. Half the intersexes appeared to be closer to the female phenotype, and the other half were closer to males.The gonads of all animals contained seminiferous tubules lined by Sertoli cells. No germ cells were present. (Information collated by Helen Axtoll, Uppsala, March 1998)

Genetic testing: Simon et al. (2020): "A diagnostic PCR was developed for simultaneous genotyping of carriers for this variant [see Molecular basis] and determination of their genetic sex. . . . Our findings enable for the first time a precise genetic diagnosis for polledness and PIS in goats and add a further genomic feature to the complexity of the PIS phenomenon."

Associated genes: