Length variation of CAG repeats in Sry across populations of Mus domesticus

Abstract

Sry is the Y Chromosome (Chr)-linked, sex-determining locus responsible for testis determination in mammals (Gubbay et al. 1990; Koopman et al. 1990, 1991; Sinclair et al. 1990). The gene is thought to contain a single exon consisting of a central DNAbinding motif (HMG box) 79 amino acids in length, and flanking sequences. The DNA sequence of the HMG domain is conserved across species of marsupial and placental mammals (Foster et al. 1992; Gubbay et al. 1990; Sinclair et al. 1990; Whitfield et al. 1993). However, flanking regions are not conserved even at lower taxonomic levels (Tucker and Lundrigan 1993; Whitfield et al. 1993). In Old World mice and rats (subfamily Murinae), for example, the carboxy non-box region contains both perfect and imperfect intervals of the trinucleotide repeat, CAG, and varies in length from 92 amino acids in the African rat (Hylomyscus alleni) to 313 amino acids in the house mouse (Mus musculus). Significant length variation is evident even when comparing Mus rausculus with its sibling species, Mus domesticus. The carboxy nonbox region in the latter species is considerably shorter, from 153 to 155 amino acids (Coward et al. 1994). Experiments investigating sex determination in mice have involved the transfer of the Mus domesticus Y Chr onto the genetic background of C57BL/6J, a standard inbred laboratory mouse strain consisting of a mixture of the genomes of Mus musculus and Mus domesticus; the Y Chr of C57BL/6J is of Asian Mus musculus origin (Nagamine et al. 1992; Tucker et al. 1992). The transfer of different Mus domesticus Y Chrs onto the C57BL/6J background can result in either sex reversal, delayed development of the testicular cord, or normal development (Biddle and Nishioka 1988; Biddle et al. 1991; Eicher et al. 1982; Eicher 1994; Nagamine et al. 1987; Washburn and Eicher 1983, 1989; Washburn et al. 1990). Recent studies have shown that Sry from Mus musculus and Mus domesticus differs in three respects: (1) there are seven single base pair differences, including a C-to-T transitional mutation at nucleotide position 9906 (numbers for nucleotide positions throughout the paper refer to the base pair positions of Sry in GenBank entry X67204) that results in the replacement of the amino acid glutamine in Mus musculus with a stop codon in Mus domesticus; (2) Mus musculus has one additional CAC repeat (8808-8810); and (3)there are differences in the number of CAG repeats in the intervals 8733-8765 and 8811-8846 (Coward et al. 1994). However, only the number of CAG repeats in the interval 8811-8846 has been found to vary within Mus domesticus (Coward et al. 1994). This variation is correlated with the occurrence of delayed testis development and sex reversal when Mus domesticus Sry alleles are placed on a C57BL/6J genetic background, i.e., C57BL/6J and the normal functioning Mus domesticus alleles have 12 CAG repeats in the interval 8811-8846, a Mus domesticus variant (AKR/J), which when crossed with C57BL/6J results in