In other species: dog , domestic cat , ass (donkey) , horse , pig , llama , taurine cattle , goat , rabbit , alpaca , raccoon dog , Arctic fox

Categories: Pigmentation phene , Mortality / aging (incl. embryonic lethal)

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 172800 (trait) , 164920 (gene)

Mendelian trait/disorder: yes

Disease-related: no

Key variant known: yes

Year key variant first reported: 2023

Cross-species summary: The dominant white gene is one of a number of genes that regulate normal growth and proliferation of cells. In fact, it encodes a protein that protrudes through the cell membrane, relaying 'messages' across the membrane, from outside to inside the cell. The transmembrane domain of the protein is a receptor for a growth factor (a protein produced by one type of cell, that acts on another type of cell). The domain inside the cell has tyrosine kinase activity. When a growth factor binds to the receptor on the outside of the cell, this stimulates tyrosine kinase activity inside the cell, which sets off a cascade of phosphorylations, resulting in activation of transcription factors, which in turn activate genes, resulting in multiplication of stem cells, including melanocyte precursor cells, in the developing embryo. This whole process is known as a signal transduction pathway. During embryonic development, the melanosome precursor cells migrate from the neural crest down either side of the body. Under normal circumstances, they eventually meet at the centre of the belly. The cells then proliferate in all directions until they meeting neighbouring cells, thereby filling up all available areas, resulting in a solid mass of melanocytes over the entire body. The dominant white allele produces a defective transmembrane protein which is unable to relay 'messages', resulting in a lack of melanocytes, and hence white coat colour. An interesting aspect of the dominant white gene is that if it is activated at the wrong time, the result can be excess and uncontrolled proliferation of stem cells; in other words, cancer. In fact, at some time in the past, a feline retrovirus (the Hardy-Zuckerman 4 feline sarcoma virus) 'picked up' (by transduction) a copy of the dominant white gene from a cat, and incorporated this gene into its own genome. When this retrovirus infects cats, it activates its own copy of the gene at inappropriate times, causing sarcoma - a malignant tumour of cells derived from connective tissue. Retroviral genes that cause cancer are called oncogenes. The original host version of an oncogene is called a proto-oncogene. Thus, the dominant white gene is actually a proto-oncogene. In this particular case, the oncogene was discovered and named v-kit (where 'v' indicates a viral version of the gene) long before its association with white coat colour was established. The corresponding proto-oncogene is called c-kit, where 'c' stands for cellular. After the discovery and cloning of v-kit in the feline retrovirus by Besmer et al. (1986; Nature 320:415-421), c-kit was identified and mapped first in humans, by Mattei et al. (1987; Cytogenetics and Cell Genetics 46:657 only), and then in mice (Chabot et al., 1988; Nature 335:88-89, 1988), where it was shown to be identical with the long-recognised white-spotting (W) locus. Three years later, Giebel and Spritz (1991; Proceedings of the National Academy of Sciences 88:8696-8699) showed that mutations at the c-kit gene in humans cause piebaldism, which is the human homologue of white spotting (see the MIM entry at the top of this page)

Species-specific description: Zhang et al. (2023) "carried out a population genomic analysis of 38 white and 59 non-white-coated yak for the identification of genomic regions associated with the white coat phenotype. By performing selection sweep analysis and genome-wide association study (GWAS), we identified both Cs6 and Cs29 alleles [see OMIA:001576-9913] in all white yak with three genotypes that showed an ~2-fold increase in copy number variations (CNVs) relative to colour-sidedness cattle. Phylogenetic analysis of candidate regions suggested the origin of the yak Cs alleles from taurine cattle via interspecific introgression."

Molecular basis: Zhang et al. (2023)" identified two types of CNVs around the KIT gene that was potentially associated with the white coat phenotype in yak. The two CNVs were defined as Yak_CNV1 of an ~520 kb segment (Chr6:51,941,217–52,461,888) and Yak_CNV2 of an internal ~141 kb segment with an additional increase in normalized coverage (Chr6:51,965,932–52,107,853) ... . Yak_CNV1 contained the KIT gene, whilst Yak_CNV2 was located downstream of the KIT gene. Normalized read depths confirmed four to 12 copies of Yak_CNV2 but two, four or eight copies of Yak_CNV1 in the genomes of Tianzhu White yak, whereas non-white-coated yak always exhibited a normal coverage ... . There were two types of combinations of these two CNVs in white yak: type I individuals carried Yak_CNV1 and Yak_CNV2, whilst type II animals only had Yak_CNV2... . Taurine_CNV1 and Taurine_CNV2 [see OMIA:001576-9913] were homologous to Yak_CNV1 and Yak_CNV2 on Chr6 and Chr29, respectively, and both were found in yak and cattle, whilst Taurine_CNV3 was only present on Chr29 in yak.

Breed: Tianzhu White Yak, China (Yak (domestic)) (VBO_0016828).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: