Evolutionary Implications of Incomplete Human X-chromosome Inactivation: Population Genetic Analyses of the KAL1 Gene
Maranville, Joseph C.1,2; Perry, George H.1,2,3; and Verrelli, Brian C.1,2
2School of Life Sciences, Arizona State University; 2Center for Functional Evolutionary Genomics, The Biodesign Institute at Arizona State University; 3School of Human Evolution and Social Change, Arizona State University
The traditional view that transcription of all genes is silenced on one of two X-chromosomes in female mammals has recently been challenged by a study estimating that ~25% of human X-chromosome genes escape inactivation. To shed light on the possible evolutionary implications of escape from X-chromosome inactivation, we compared single nucleotide polymorphism (SNP) allele frequency patterns between genes that escape inactivation and genes that are inactivated in three populations of Chinese, European and African descent. Using the SNP patterns at neutrally evolving intergenic regions on the X-chromosome as our expectation, we found that SNP patterns at escape genes have much more variation, thus implying that natural selection may favor variation at genes that escape inactivation. To directly test this hypothesis, we collected DNA sequence data in 96 individuals from ten ethnically and geographically diverse human populations for KAL1, an X-chromosome gene that escapes inactivation. Although KAL1 has been well studied due to its involvement in the sex-linked genetic disorder Kallman Syndrome, which is characterized by impaired reproductive development and an inability to smell, it is unclear why variation is so frequent, and possibly even adaptive, at this gene. Consequently, human population genetic analyses of disease genes, like KAL1, can benefit the medical community in revealing whether variation may be beneficial at these genes to explain why some of these diseases are higher in frequency than is naturally expected.