Hematopoietic stem-cell transplantation (HSCT) is a potentially lifesaving therapy for several blood cancers and other diseases. For patients without a suitable related HLA-matched donor, unrelated-donor registries of adult volunteers and banked umbilical cord–blood units, such as the Be the Match Registry operated by the National Marrow Donor Program (NMDP), provide potential sources of donors. Our goal in the present study was to measure the likelihood of finding a suitable donor in the U.S. registry. Using human HLA data from the NMDP donor and cord-blood-unit registry, we built population-based genetic models for 21 U.S. racial and ethnic groups to predict the likelihood of identifying a suitable donor (either an adult donor or a cord-blood unit) for patients in each group. The models incorporated the degree of HLA matching, adult-donor availability (i.e., ability to donate), and cord-blood-unit cell dose. Our models indicated that most candidates for HSCT will have a suitable (HLA-matched or minimally mismatched) adult donor. However, many patients will not have an optimal adult donor — that is, a donor who is matched at high resolution at HLA-A, HLA-B, HLA-C, and HLA-DRB1. The likelihood of finding an optimal donor varies among racial and ethnic groups, with the highest probability among whites of European descent, at 75%, and the lowest probability among blacks of South or Central American descent, at 16%. Likelihoods for other groups are intermediate. Few patients will have an optimal cord-blood unit — that is, one matched at the antigen level at HLA-A and HLA-B and matched at high resolution at HLA-DRB1. However, cord-blood units mismatched at one or two HLA loci are available for almost all patients younger than 20 years of age and for more than 80% of patients 20 years of age or older, regardless of racial and ethnic background. Most patients likely to benefit from HSCT will have a donor. Public investment in donor recruitment and cord-blood banks has expanded access to HSCT. (Funded by the Office of Naval Research, Department of the Navy, and the Health Resources and Services Administration, Department of Health and Human Services.)

Whole genome comparisons identified introgression from archaic to modern humans. Our analysis of highly polymorphic human leukocyte antigen (HLA) class I, vital immune system components subject to strong balancing selection, shows how modern humans acquired the HLA-B*73 allele in west Asia through admixture with archaic humans called Denisovans, a likely sister group to the Neandertals. Virtual genotyping of Denisovan and Neandertal genomes identified archaic HLA haplotypes carrying functionally distinctive alleles that have introgressed into modern Eurasian and Oceanian populations. These alleles, of which several encode unique or strong ligands for natural killer cell receptors, now represent more than half the HLA alleles of modern Eurasians and also appear to have been later introduced into Africans. Thus, adaptive introgression of archaic alleles has significantly shaped modern human immune systems.

We have calculated six-locus high resolution HLA A∼C∼B∼DRB3/4/5∼DRB1∼DQB1 haplotype frequencies using all Be The Match(®) Registry volunteer donors typed by DNA methods at recruitment. Mixed resolution HLA typing data was inputted to a modified expectation-maximization (EM) algorithm in the form of genotype lists generated by interpretation of primary genomic typing data to the IMGT/HLA v3.4.0 allele list. The full cohort consists of 6.59 million subjects categorized at a broad race level. Overall 25.8% of the individuals were typed at the C locus, and 5.2% typed at the DQB1 locus, while all individuals were typed for A, B, DRB1. We also present a subset of 2.90 million subjects with detailed race/ethnic information mapped to 21 population subgroups, 64.1% of which have primary DNA typing data across at least A, B, and DRB1 loci. Sample sizes at the detailed race level range from 1,242,890 for European Caucasian to 1,376 Alaskan Native or Aleut. Genetic distance measurements show high levels of HLA genetic divergence among the 21 detailed race categories, especially among the eight Asian-American populations. These haplotype frequencies will be used to improve match predictions for donor selection algorithms for hematopoietic stem cell transplantation and improve the accuracy in modeling registry match rates.