Sex determination: a hypothesis based on noncoding DNA.

Abstract

Certain recent models of sex determination in mammals, Drosophila melanogaster, Caenorhabditis ekgans, and snakes are examined in the light of the hypothesis that the relevant genetic regulatory mechanisms are similar and interrelated. The proposed key element in each of these instances is a noncoding DNA sequence, which serves as a high-affinity binding site for a repressor-like molecule regulating the activity of a major "sex-determining" gene. On this basis it is argued that, in several eukaryotes, (i) certain DNA sequences that are sex-determining are noncoding, in the sense that they are not the structural genes of a sex-determining protein; (it) in some species these noncoding sequences are present in one sex and absent in the other, while in others their copy number or accessibility to regulatory molecules is significantly unequal between the two sexes; and (fii) this inequality determines whether the embryo develops into a male or a female.Sex determination in Drosophila melanogaster (1-4) and Caenorhabditis elegans (5) appears to be based on interactions among a small number of genes, with the level of activity of one gene being of primary importance. Consequently, it becomes feasible to look upon the choice of sexual phenotype in development as being mediated through a kind of genetic switch that opens up one or the other of two alternative pathways. If so, one is then led to inquire about the nature of the regulatory elements that might constitute such a switch.If sex determination is based on a small number of critical genes and on an "either/or" mechanism, it is reasonable to expect both single-gene mutations and, occasionally, environmental perturbations to shift sexual development from one pathway to the other. Mutations that transform sex in this manner are known in D. melanogaster, in C. elegans, and in mammals. In some reptiles sex is determined by the temperature at which egg incubation occurs. The sharp temperature thresholds seen in these experiments (6, 7) and the absence of intersexes or significant egg mortality suggest that not only a small number of genes might be involved but also a high degree of cooperativity in the relevant regulatory processes.On the basis of a recent model for mammalian sex determination (8, 9) and related results (2), I wish to suggest that certain noncoding DNA sequences could be responsible for the choice of sexual phenotype during development. The term "noncoding" sequence is used in this paper to mean that the DNA sequence is not the structural gene for a sexdetermining protein. Rather, its role in sex determination is to bind a repressor-like molecule and, thereby, to regulate indirectly the activity of a "sex-determining" gene. "Repressor" denotes a regulatory molecule that has high affinity for the noncoding sequence(s) but whose primary role is in controlling the activity of a major sex-determining gene.THE MODELS Mammals. There are at least three observations that must be faced by any model of primary sex determination in mammals: (i) the failure...

Conserved synteny between the chicken Z sex chromosome and human chromosome 9 includes the male regulatory gene <i>DMRT1:</i> a comparative (re)view on avian sex determination

“…In this light, avian sex determination may resemble the situation in C. elegans, where the dosage of the X-linked Xol-1 gene acts as a primary switch (Miller et al, 1988). Dosage-based sex determination mechanisms also exist in Drosophila and may operate in other nonmammalian vertebrates (Chandra, 1985). In contrast, the upstream regulatory gene on the mammalian Y chromosome, SRY, induces testes differentiation in a dosage-insensitive way.…”

Potential genetic functions of tandem repeated DNA sequence blocks in the human genome are based on a highly conserved ?chromatin folding code?

“…In the field vole, GATA-and GACA-repeats characterize the compactness of the X chromosome (Nanda et al 1988). Since (GATA)n-blocks are associated with the sex-determining locus in mouse and yeast (Jones 1983), it has been postulated that the determination of heterogametic sex development will at least partly be encoded by this repetitive simple sequence family (Chandra 1985). Although this hypothesis of sex determination is weakened by the fact that on the human Y chromosome the position of the sex determining gene TDF (Page et al 1987) seems not to be related to the G A T A repeat family of this There is a precise and reproducible correspondence between all three banding patterns (Burkholder et al 1988) chromosome (Arnemann et al 1986), it is intriguing that this simple repeat family is associated with chromosome regions of one or the other sex chromosome with a highly non-random incidence.…”

XY females in <i>Microtus cabrerae</i> (Rodentia, Microtidae): a case of possibly Y-linked sex reversal

“…andEicher andWashburn (1986). or (2) a deletion of the masculinizing sequences (Bkm sequences) in the Y chromosome, according to the model of Chandra (1984 and1985). In this species these genes, or these sequences, could be located either on the short arm of the Y chromosome, or on the long arm near the centromere, as suggested by the presence of normal males which have deletions of almost the entire long arm.…”