Special feature

Call for a worldwide survey of human genetic diversity: A vanishing opportunity for the Human Genome Project

Alzheimer disease (AD) is the most common form of senile dementia, with high incidence late in life in many populations including Caribbean Hispanic (CH) populations. Such admixed populations, descended from more than one ancestral population, can present challenges for genetic studies, including limited sample sizes and unique analytical constraints. Therefore, CH populations and other admixed populations have not been well represented in studies of AD, and much of the genetic variation contributing to AD risk in these populations remains unknown. Here, we conduct genome-wide analysis of AD in multiplex CH families from the Alzheimer Disease Sequencing Project (ADSP). We developed, validated, and applied an implementation of a logistic mixed model for admixture mapping with binary traits that leverages genetic ancestry to identify ancestry-of-origin loci contributing to AD. We identified three loci on chromosome 13q33.3 associated with reduced risk of AD, where associations were driven by Native American (NAM) ancestry. This AD admixture mapping signal spans the FAM155A, ABHD13, TNFSF13B, LIG4, and MYO16 genes and was supported by evidence for association in an independent sample from the Alzheimer’s Genetics in Argentina—Alzheimer Argentina consortium (AGA-ALZAR) study with considerable NAM ancestry. We also provide evidence of NAM haplotypes and key variants within 13q33.3 that segregate with AD in the ADSP whole-genome sequencing data. Interestingly, the widely used genome-wide association study approach failed to identify associations in this region. Our findings underscore the potential of leveraging genetic ancestry diversity in recently admixed populations to improve genetic mapping, in this case for AD-relevant loci.

Microhaplotype loci (microhaps, MHs) are a novel type of molecular marker of less than 300 nucleotides, defined by two or more closely linked SNPs associated in multiple allelic combinations. The value of these markers is enhanced by massively parallel sequencing (MPS), which allows the sequencing of both parental haplotypes at each of the many multiplexed loci. This review describes the features of these multi-SNP markers and documents their value in forensic genetics, focusing on individualization, biogeographic ancestry inference, and mixture deconvolution. Foreseeable applications also include missing person identification, relationship testing, and medical diagnostic applications. The technique is not restricted to humans.

We have estimated human leukocyte antigen (HLA) haplotype frequencies using the maximum likelihood mode, which accommodates typing ambiguities. The results of the frequency distribution of the 7015 haplotypes obtained are presented here. These include a total of 114 HLA-A, 185 HLA-B, and 76 HLA-DRB1 unique alleles at each locus. Across all populations, although the most common individual HLA alleles were HLA-A^∗02:01 (29.0%), HLA-B^∗07:02 (11.4%), and HLA-DRB1^∗07:01 (15.9%), the most frequent haplotype was found to be HLA-A^∗01:01∼B^∗08:01∼DRB1^∗03:01.

The Human Genome Diversity Project was intended to be a large-scale effort to sample and archive human genetic variation. It was initially proposed by geneticists and evolutionary biologists in the early 1990s and was soon met by strong criticism. These criticisms came from multiple fronts, including biological and cultural anthropologists as well as indigenous rights activists and community members. Project organizers, who identified as antiracist and uninterested in reaping commercial benefits, were surprised to learn that many of these critics perceived the project as racist and neocolonial. These concerns led the initiative to falter, particularly in the United States. While the Human Genome Diversity Project did not achieve its original aims, it demonstrated the need to attend to the intertwined ethical and epistemological challenges of investigating human difference in a genomic age.