Biased Gene Conversion Skews Allele Frequencies in Human Populations,Increasing the Disease Burden of Recessive Alleles

Gene conversion results in the nonreciprocal transfer of genetic information between two recombining sequences, and there is evidence that this process is biased toward G and C alleles. However, the strength of GC-biased gene conversion (gBGC) in human populations and its effects on hereditary disease have yet to be assessed on a genomic scale. Using high-coverage whole-genome sequences of African hunter-gatherers, agricultural populations, and primate outgroups, we quantified the effects of GC-biased gene conversion on population genomic data sets. We find that genetic distances (F_ST and population branch statistics) are modified by gBGC. In addition, the site frequency spectrum is left-shifted when ancestral alleles are favored by gBGC and right-shifted when derived alleles are favored by gBGC. Allele frequency shifts due to gBGC mimic the effects of natural selection. As expected, these effects are strongest in high-recombination regions of the human genome. By comparing the relative rates of fixation of unbiased and biased sites, the strength of gene conversion was estimated to be on the order of Nb ≈ 0.05 to 0.09. We also find that derived alleles favored by gBGC are much more likely to be homozygous than derived alleles at unbiased SNPs (+42.2% to 62.8%). This results in a curse of the converted, whereby gBGC causes substantial increases in hereditary disease risks. Taken together, our findings reveal that GC-biased gene conversion has important population genetic and public health implications.     

Polypharmacy in the management of patients with schizophrenia on risperidone in a tertiary-care hospital in Malaysia

The present study was conducted primarily to determine the occurrence of polypharmacy in patients with schizophrenia on risperidone. The secondary aim was to ascertain the incidence of inappropriate prescribing with anticholinergics. A retrospective review of the medical records of all patients who were being followed up at the out-patient clinic of a tertiary-care hospital in Malaysia was conducted. Only patients who were being prescribed risperidone between 1 June 2008 and 31 December 2008 were included in the study. Demographic data such as patient’s age, gender and race were obtained from the patient’s medical records. In total, 113 patients met the selection criteria. Polypharmacy was found to occur in 34 patients (30.09%), with the majority (76.47%) being on two antipsychotics. In total, 27 patients (34.18%) on monotherapy with risperidone were prescribed an anticholinergic on scheduled dosing, while 19 patients (24.05%) were prescribed it on an as-needed basis. Of the patients on polypharmacy, 26 (76.47%) were on scheduled dosing of anticholinergics, while three (8.82%) were taking the medication on an as-needed basis. Polypharmacy should be avoided, and the use of anticholinergics should be closely reviewed. By adopting more efficient prescribing practices, costs can be reduced and financial resources can instead be channelled towards more beneficial areas for the patients.     

Patterns of nucleotide and haplotype diversity at ICAM-1 across global human populations with varying levels of malaria exposure

Malaria is one of the strongest selective pressures in recent human evolution. African populations have been and continue to be at risk for malarial infections. However, few studies have re-sequenced malaria susceptibility loci across geographically and genetically diverse groups in Africa. We examined nucleotide diversity at Intercellular adhesion molecule-1 (ICAM-1), a malaria susceptibility candidate locus, in a number of human populations with a specific focus on diverse African ethnic groups. We used tests of neutrality to assess whether natural selection has impacted this locus and tested whether SNP variation at ICAM-1 is correlated with malaria endemicity. We observe differing patterns of nucleotide and haplotype variation in global populations and higher levels of diversity in Africa. Although we do not observe a deviation from neutrality based on the allele frequency distribution, we do observe several alleles at ICAM-1, including the ICAM-1 ^Kilifi allele, that are correlated with malaria endemicity. We show that the ICAM-1 ^Kilifi allele, which is common in Africa and Asia, exists on distinct haplotype backgrounds and is likely to have arisen more recently in Asia. Our results suggest that correlation analyses of allele frequencies and malaria endemicity may be useful for identifying candidate functional variants that play a role in malaria resistance and susceptibility.     

Exonuclease I of Saccharomyces cerevisiae functions in mitotic recombination in vivo and in vitro.

We previously described a 5'-3' exonuclease required for recombination in vitro between linear DNA molecules with overlapping homologous ends. This exonuclease, referred to as exonuclease I (Exo I), has been purified more than 300-fold from vegetatively grown cells and copurifies with a 42-kDa polypeptide. The activity is nonprocessive and acts preferentially on double-stranded DNA. The biochemical properties are quite similar to those of Schizosaccharomyces pombe Exo I. Extracts prepared from cells containing a mutation of the Saccharomyces cerevisiae EXO1 gene, a homolog of S. pombe exo1, had decreased in vitro recombination activity and when fractionated were found to lack the peak of activity corresponding to the 5'-3' exonuclease. The role of EXO1 on recombination in vivo was determined by measuring the rate of recombination in an exo1 strain containing a direct duplication of mutant ade2 genes and was reduced sixfold. These results indicate that EXO1 is required for recombination in vivo and in vitro in addition to its previously identified role in mismatch repair.