Inferences on selection and mutation from substitution rate differences in both recombining and non-recombining regions of sex chromosomes

Gerrard, David Thomas (2005). Inferences on selection and mutation from substitution rate differences in both recombining and non-recombining regions of sex chromosomes. University of Birmingham. Ph.D.

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Abstract

This thesis comprises an introductory chapter and four experimental chapters. The introduction is a literature review of the forms and evolution of sex chromosomes and of the molecular evolutionary processes that affect sex-linked genes. Special attention is paid to the commonly and convergently evolved trait of the degenerative Y, whereby these non-recombining chromosomes progressively lose functional genetic material over time. The differences in inheritance, in physical structure and in genetic composition that exist between the sex chromosomes and autosomes, between the X and the Y and even along a single sex chromosome may allow us to partition and contrast the effects of the many hypothesised mechanisms that govern the evolution of entire genomes.

The experimental chapters are presented in chronological order but also approach a finer scale; from the generation of a genomic distribution, through an investigation of a class of genes down to detailed analyses of specific sex linked genes.

Chapter II deals with sequences in the pseudo-autosomal region (PAR) of the mammalian sex chromosomes, the only region in which the X and Y chromosomes are able to recombine. Due to the small size of the PAR, the recombination rate per nucleotide is higher than any other comparable sized region in the genome. A link between recombination and mutation, suggested by several other studies, is investigated using primate sequence. The chapter describes how 51 pairs of human and orangutan DNA sequences were aligned to generate a distribution of divergence values between these two species. This distribution was then used to show that silent sites in the PAR are evolving at an abnormally high rate; consistent with the hypothesis that recombination is mutagenic. A paper published in the journal Gene and using this result is included after the chapter.

In contrast to the previous chapter, Chapter III investigates three pairs of X and Y linked genes that have not recombined with each other for tens of millions of years. By sequencing and aligning these genes in a range of primates, I was able to test for differences in the rate of adaptive evolution between different sites along the sequence. As well as a reduced level of selective constraint on the Y chromosome relative to the X, I found evidence that positive selection is still able to drive the evolution of genes in a non-recombining Y chromosome after such a long time. This result is surprising and contradictory to several predictions of the demise of Y chromosomes. Chapter III has been submitted to the journal Molecular Biology and Evolution.

In Chapter IV these methods are applied to Amelogenin (AMEL), the gene that helps to lay down tooth enamel. This gene used to lie inside the sex chromosome PAR but since monkeys diverged from lemurs, it has existed as X and Y forms in the lineage leading to humans. In attempting to discern if the Y linked amelogenin is still under selection or evolving neutrally, several conflicting patterns were discovered. Whilst some of the primate AMEL sequences appeared to be recombining, it was found to be more likely that recurrent mutation at specific sites in an otherwise conserved sequence were generating a false signal. Y linked amelogenin is still conserved, but is adjusting to life on a non-recombining chromosome with its associated mutation bias and reduction in constraint.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):