title: Microsatellite-encoded domain in rodent Sry functions as a genetic capacitor to enable the rapid evolution of biological novelty.
abstract: The male program of therian mammals is determined by Sry, a transcription factor encoded by the Y chromosome. Specific DNA binding is mediated by a high mobility group (HMG) box. Expression of Sry in the gonadal ridge activates a Sox9-dependent gene regulatory network leading to testis formation. A subset of Sry alleles in superfamily Muroidea (order Rodentia) is remarkable for insertion of an unstable DNA microsatellite, most commonly encoding (as in mice) a CAG repeat-associated glutamine-rich domain. We provide evidence, based on an embryonic pre-Sertoli cell line, that this domain functions at a threshold length as a genetic capacitor to facilitate accumulation of variation elsewhere in the protein, including the HMG box. The glutamine-rich domain compensates for otherwise deleterious substitutions in the box and absence of nonbox phosphorylation sites to ensure occupancy of DNA target sites. Such compensation enables activation of a male transcriptional program despite perturbations to the box. Whereas human SRY requires nucleocytoplasmic shuttling and coupled phosphorylation, mouse Sry contains a defective nuclear export signal analogous to a variant human SRY associated with inherited sex reversal. We propose that the rodent glutamine-rich domain has (i) fostered accumulation of cryptic intragenic variation and (ii) enabled unmasking of such variation due to DNA replicative slippage. This model highlights genomic contingency as a source of protein novelty at the edge of developmental ambiguity and may underlie emergence of non-Sry-dependent sex determination in the radiation of Muroidea.
authors.affiliation: Department of Biochemistry, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Yen-Shan
authors.initials: YS
authors.lastname: Chen
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Racca
authors.forename: Paul W
authors.initials: PW
authors.lastname: Sequeira
authors.forename: Nelson B
authors.initials: NB
authors.lastname: Phillips
authors.forename: Michael A
authors.initials: MA
authors.lastname: Weiss
mesh_terms: D000818:Animals; D005075:Biological Evolution; D015153:Blotting, Western; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D002942:Circular Dichroism; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D031541:Fluorescence Resonance Energy Transfer; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D053263:Gene Regulatory Networks / Q000235:genetics*; D024742:HMG-Box Domains / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018895:Microsatellite Repeats / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012377:Rodentia / Q000235:genetics*; D019849:Sex Determination Processes / Q000235:genetics*; D051876:Sex-Determining Region Y Protein / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D018911:Trinucleotide Repeats / Q000235:genetics
chemical_list: D051876:Sex-Determining Region Y Protein; C497746:Sry protein, mouse; D004247:DNA
keywords: nucleocytoplasmic trafficking; protein–DNA recognition; sexual dimorphism; transcriptional activation; triplet expansion
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