Population Genomic Analysis of ALMS1 in Humans Reveals a Surprisingly Complex Ev

[I2a1a]

Mutations in the human gene ALMS1 result in Alstro?m Syndrome, which presents with early childhood obesity and
insulin resistance leading to Type 2 diabetes. Previous genomewide scans for selection in the HapMap data based on
linkage disequilibrium and population structure suggest that ALMS1 was subject to recent positive selection. Through
a detailed population genomic analysis of existing genomewide data sets and new resequencing data obtained in
geographically diverse populations, we find that the signature of selection at ALMS1 is considerably more complex than
what would be expected for an idealized model of a selective sweep acting on a newly arisen advantageous mutation.
Specifically, we observed three highly divergent and globally dispersed haplogroups, two of which carry a set of seven
derived nonsynonymous single nucleotide polymorphisms that are nearly fixed in Asian populations. Our data suggest
that the interaction of human demographic history and positive selection on standing variation in Eurasian populations
approximately 15 thousand years ago parsimoniously explains the spectrum of extant ALMS1 variation. These results
provide new insights into the evolutionary history of ALMS1 in humans and suggest that selective events identified in
genomewide scans may be more complex than currently appreciated.