Evidence for Widespread Convergent Evolution around Human Microsatellites

Abstract

Microsatellites are a major component of the human genome, and their evolution has been much studied. However, the evolution of microsatellite flanking sequences has received less attention, with reports of both high and low mutation rates and of a tendency for microsatellites to cluster. From the human genome we generated a database of many thousands of (AC)n flanking sequences within which we searched for common characteristics. Sequences flanking microsatellites of similar length show remarkable levels of convergent evolution, indicating shared mutational biases. These biases extend 25–50 bases either side of the microsatellite and may therefore affect more than 30% of the entire genome. To explore the extent and absolute strength of these effects, we quantified the observed convergence. We also compared homologous human and chimpanzee loci to look for evidence of changes in mutation rate around microsatellites. Most models of DNA sequence evolution assume that mutations are independent and occur randomly. Allowances may be made for sites mutating at different rates and for general mutation biases such as the faster rate of transitions over transversions. Our analysis suggests that these models may be inadequate, in that proximity to even very short microsatellites may alter the rate and distribution of mutations that occur. The elevated local mutation rate combined with sequence convergence, both of which we find evidence for, also provide a possible resolution for the apparently contradictory inferences of mutation rates in microsatellite flanking sequences.

A highly divergent microsatellite facilitating fast and accurateDRBhaplotyping in humans and rhesus macaques

“…To what extent the repeat composition may have a direct or indirect influence on the low mutation rate of the adjacent exon 2 segment of the DRB7 pseudogene is not well understood at present. It has been proposed, for example, that microsatellites near genes may increase and probably also decrease local mutation rates (45). Interestingly, exon 2 of the DRB7 pseudogene, present on the only shared DR region configuration of humans and chimpanzees, is highly conserved between both species.…”

Dynamic mutations as digital genetic modulators of brain development, function and dysfunction

“…Studies that examined trinucleotide repeat lengths in primates and other species found that humans have greater repeat lengths (and greater variability between individuals-although limited variance may be the consequence of captive breeding or restricted population sampling in the other species examined) than other great apes, which in turn have longer repeat sequences than rodents. (16)(17)(18)21,22,(40)(41)(42) Thus the mechanism whereby more variability arose in this primate lineage, possibly via associated mutations regulating fidelity and proof-reading during DNA replication, could be of significance. Furthermore, the unique aspect of human evolution is that it has involved developmentally mediated expansion of specific brain regions, particularly the cerebral cortex, as well as subsequent enhancement of cognitive abilities, and therefore the relationship between TRP evolution and the genetic regulation of neurodevelopment and neural plasticity, is a question worth exploring using a combination of genomics and neuroscience approaches.…”

Traffic of genetic information between segmental duplications flanking the typical 22q11.2 deletion in velo-cardio-facial syndrome/DiGeorge syndrome

“…Finally, we should note that we have excluded all simple repeats including AT-rich repeats from our analysis because of possible alignment artifacts. However, positions close to simple repeats exhibit an increased rate of gene conversion in the human genome (Vowles and Amos 2004), and it is thus possible that simple repeats including those in LCR22-2/LCR22-4 can potentially also undergo concerted evolution.…”