Characterization of genetic variation in genes adjacent to the pseudoautosomal region on the X and Y chromosomes; implications for analysis of next generation sequencing data
Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
During the course of evolution one strand of a pair of autosomes obtained a sex-determining gene and subsequently developed to the Y chromosome. Recombination between the sex chromosomes does not occur except on the tips of the chromosomes between regions calld pseudoautosomal regions (PARs). Thus these regions behave like autosomes and the PARs are therefore not inherited in a sex-linked pattern. The PARs of the Y and X chromosomes crossover at least once during each male meiosis event and this makes the recombination rate much higher for these regions in comparison to the rest of the genome. But the exact borders of recombination between the PARs have not been defined. Thus it is hypothesised that the genes loacted directly below PAR1 may be exposed to variation due to recombination with Y-linked pseudogenes. The genes located immediately below PAR1 encode for proteins involved in metabolic processes and a mutation in these genes may cause inherited metabolic diseases.
To test this hypothesis a family of then members was chosen where previous whole genome sequencing (WGS) had identified variations in the genes immediately below the PAR1. The exons of the genes centromeric to PAR1 on the X chromosome were sequenced using Sanger sequencing so two questions could be answered. The first question was if the mutations identified with WGS on the X chromosome may have been false positives due to miss-mapping of pseudogenes on the Y chromosome. And the second question to be answered was to determine if the genes centromeric to PAR are exposed to variations due to recombination with the Y-linked pseudogenes. The first question was answered by making a direct comparison between the variations identified with the different sequencing mathods. The second question was answered by following the inheritance patterns of the mutation. If the genes centromeric to PAR are exposed to variations then there would be an irregular pattern of inheritance of mutations.
The results of this work show that the variations identified with WGS completely matched the results of the Sanger sequencing for four of the five examined genes. It can hence be concluded that for these four genes the variations identified on the X-chromosome with WGS were correctly mapped. The results also show and inheritance pattern of these variations that would be expected if no recombination occurred with the Y-linked pseudogenes and it can thus be concluded that the genes centromeric to PAR1 are located outside of PAR1.
Place, publisher, year, edition, pages
genetic variation, pseudoautosomal, chromosome
Engineering and Technology
IdentifiersURN: urn:nbn:se:kth:diva-163695OAI: oai:DiVA.org:kth-163695DiVA: diva2:801911