Multiple selective sweeps of ancient polymorphisms in and around LTα located in the MHC class III region on chromosome 6.

BACKGROUND: Lymphotoxin-α (LTα), located in the Major Histocompatibility Complex (MHC) class III region on chromosome 6, encodes a cytotoxic protein that mediates a variety of antiviral responses among other biological functions. Furthermore, several genotypes at this gene have been implicated in the onset of a number of complex diseases, including myocardial infarction, autoimmunity, and various types of cancer. However, little is known about levels of nucleotide variation and linkage disequilibrium (LD) in and near LTα, which could also influence phenotypic variance. To address this gap in knowledge, we examined sequence variation across ~ 10 kilobases (kbs), encompassing LTα and the upstream region, in 2039 individuals from the 1000 Genomes Project originating from 21 global populations. RESULTS: Here, we observed striking patterns of diversity, including an excess of intermediate-frequency alleles, the maintenance of multiple common haplotypes and a deep coalescence time for variation (dating > 1.0 million years ago), in global populations. While these results are generally consistent with a model of balancing selection, we also uncovered a signature of positive selection in the form of long-range LD on chromosomes with derived alleles primarily in Eurasian populations. To reconcile these findings, which appear to support different models of selection, we argue that selective sweeps (particularly, soft sweeps) of multiple derived alleles in and/or near LTα occurred in non-Africans after their ancestors left Africa. Furthermore, these targets of selection were predicted to alter transcription factor binding site affinity and protein stability, suggesting they play a role in gene function. Additionally, our data also showed that a subset of these functional adaptive variants are present in archaic hominin genomes. CONCLUSIONS: Overall, this study identified candidate functional alleles in a biologically-relevant genomic region, and offers new insights into the evolutionary origins of these loci in modern human populations.

Correction to: Multiple selective sweeps of ancient polymorphisms in and around LTα located in the MHC class III region on chromosome 6.

After publication of our article [1] we were notified that a few duplicate sentences were included on Figure 3 and Figure 4 legends.

Overlooked and Damaging Impact of Structural Racism and Implicit Bias on US Health Care: Overarching Policy Implications.

ABSTRACT: Marginalized populations, including racial and ethnic minorities, have historically faced significant barriers to accessing quality health care because of structural racism and implicit bias. A brief review and analysis of past and historic and current policies demonstrate that structural racism and implicit bias continue to underscore a health system characterized by unequal access and distribution of health care resources. Although advances in cancer care have led to decreased incidence and mortality, not all populations benefit. New policies must explicitly seek to eliminate disparities and drive equity for historically marginalized populations to improve access and outcomes.