Single haplotype admixture models using large scale HLA genotype frequencies to reproduce human admixture.

The human leukocyte antigen (HLA) is the most polymorphic region in humans. Anthropologists use HLA to trace populations' migration and evolution. However, recent admixture between populations can mask the ancestral haplotype frequency distribution. We present a statistical method based on high-resolution HLA haplotype frequencies to resolve population admixture using a non-negative matrix factorization formalism and validated using haplotype frequencies from 56 world populations. The result is a minimal set of source components (SCs) decoding roughly 90% of the total variance in the studied admixtures. These SCs agree with the geographical distribution, phylogenies, and recent admixture events of the studied groups. With the growing population of multi-ethnic individuals, or individuals that do not report race/ethnic information, the HLA matching process for stem-cell and solid organ transplants is becoming more challenging. The presented algorithm provides a framework that facilitates the breakdown of highly admixed populations into SCs, which can be used to better match the rapidly growing population of multi-ethnic individuals worldwide.

HLA Haplotypes In 250 Families: The Baylor Laboratory Results And A Perspective On A Core NGS Testing Model For The 17th International HLA And Immunogenetics Workshop.

Since their inception, the International HLA & Immunogenetics Workshops (IHIW) served as a collaborative platform for exchange of specimens, reference materials, experiences and best practices. In this report we present a subset of the results of human leukocyte antigen (HLA) haplotypes in families tested by next generation sequencing (NGS) under the 17th IHIW. We characterized 961 haplotypes in 921 subjects belonging to 250 families from 8 countries (Argentina, Austria, Egypt, Jamaica, Germany, Greece, Kuwait, and Switzerland). These samples were tested in a single core laboratory in a high throughput fashion using 6 different reagents/software platforms. Families tested included patients evaluated clinically as transplant recipients (kidney and hematopoietic cell transplant) and their respective family members. We identified 486 HLA alleles at the following loci HLA-A, -B, -C, -DRB1, -DRB3, -DRB4, -DRB5, -DQA1, -DQB1, -DPA1, -DPB1 (77, 115, 68, 69, 10, 6, 4, 44, 31, 20 and 42 alleles, respectively). We also identified nine novel alleles with polymorphisms in coding regions. This approach of testing samples from multiple laboratories across the world in different stages of technology implementation in a single core laboratory may be useful for future international workshops. Although data presented may not be reflective of allele and haplotype frequencies in the countries to which the families belong, they represent an extensive collection of 3rd and 4th field resolution level 11-locus haplotype associations of 486 alleles identified in families from 8 countries.

High resolution HLA allele and haplotype frequencies for Arab donors in the Hadassah bone marrow donor registry.

Five locus allele-level HLA-A, -B, -C, -DRB1, -DQB1 allele and haplotype frequencies have been calculated for almost 29,000 people from three Arab populations that live in Israel and were recruited as donors to the Hadassah bone marrow donor registry. These groups are of Muslim, Christian and Bedouin Arab descent which represent more than 90% of the Arabs that live in Israel. The goal of the study was to describe the HLA genetic profiles of the Hadassah Arab registry donors and investigate the utility of these donors for the local and international hematopoietic stem-cell transplant community. The results demonstrate that the analyzed Arab populations share at least seven of the top ten most frequent alleles. Comparison with other populations confirmed the proximity of the three Arab populations to each other and to the Be The Match® Middle Eastern population. Despite these similarities, some alleles are private to each of the three groups, possibly because of historical, environmental or societal events. Clinical data showed that Arab donors were HLA matched with Arab and international patients. This analysis indicates the value added by the Hadassah Arab donors to the local and global transplant community.

GRIMM: GRaph IMputation and matching for HLA genotypes.

MOTIVATION: For over 10 years allele-level HLA matching for bone marrow registries has been performed in a probabilistic context. HLA typing technologies provide ambiguous results in that they could not distinguish among all known HLA alleles equences; therefore registries have implemented matching algorithms that provide lists of donor and cord blood units ordered in terms of the likelihood of allele-level matching at specific HLA loci. With the growth of registry sizes, current match algorithm implementations are unable to provide match results in real time. RESULTS: We present here a novel computationally-efficient open source implementation of an HLA imputation and match algorithm using a graph database platform. Using graph traversal, the matching algorithm runtime is practically not affected by registry size. This implementation generates results that agree with consensus output on a publicly-available match algorithm cross-validation dataset. AVAILABILITY AND IMPLEMENTATION: The Python, Perl and Neo4j code is available at https://github.com/nmdp-bioinformatics/grimm. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Chromosome Y-encoded antigens associate with acute graft-versus-host disease in sex-mismatched stem cell transplant.

Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a curative option for blood cancers, but the coupled effects of graft-versus-tumor and graft-versus-host disease (GVHD) limit its broader application. Outcomes improve with matching at HLAs, but other factors are required to explain residual risk of GVHD. In an effort to identify genetic associations outside the major histocompatibility complex, we conducted a genome-wide clinical outcomes study on 205 acute myeloid leukemia patients and their fully HLA-A-, HLA-B-, HLA-C-, HLA-DRB1-, and HLA-DQB1-matched (10/10) unrelated donors. HLA-DPB1 T-cell epitope permissibility mismatches were observed in less than half (45%) of acute GVHD cases, motivating a broader search for genetic factors affecting clinical outcomes. A novel bioinformatics workflow adapted from neoantigen discovery found no associations between acute GVHD and known, HLA-restricted minor histocompatibility antigens (MiHAs). These results were confirmed with microarray data from an additional 988 samples. On the other hand, Y-chromosome-encoded single-nucleotide polymorphisms in 4 genes (PCDH11Y, USP9Y, UTY, and NLGN4Y) did associate with acute GVHD in male patients with female donors. Males in this category with acute GVHD had more Y-encoded variant peptides per patient with higher predicted HLA-binding affinity than males without GVHD who matched X-paralogous alleles in their female donors. Methods and results described here have an immediate impact for allo-HCT, warranting further development and larger genomic studies where MiHAs are clinically relevant, including cancer immunotherapy, solid organ transplant, and pregnancy.

The distribution of HLA haplotypes in the ethnic groups that make up the Brazilian Bone Marrow Volunteer Donor Registry (REDOME).

The Registries of Bone Marrow Donors around the world include more than 30 million volunteer donors from 57 different countries, and were responsible for over 17,000 hematopoietic stem cell transplants in 2016. The Brazilian Bone Marrow Volunteer Donor Registry (REDOME) was established in 1993 and is the third largest registry in the world with more than 4.3 million donors. We characterized HLA allele and haplotypes frequencies from REDOME comparing them with the donor self-reported race group classification. Five-locus haplotype frequencies (A~C~B~DRB1~DQB1) were estimated for each of the six race groups, resolving phase and allelic ambiguity using the expectation-maximization (EM) algorithm. The top 100 haplotypes in the race groups were separated into eight clusters of haplotypes, based on haplotype similarity, using CLUTO. We present HLA allele and haplotype frequency data from six race groups from 2,938,259 individuals from REDOME. The most frequent haplotype was the same for all groups: A*01:01g~C*07:01g~B*08:01g~DRB1*03:01g~DQB1*02:01g. Some frequent haplotypes such as A*02:01g~C*16:01g~B*44:03~DRB1*07:01g~DQB1*02:01g was not found in people with Preta (Sub-Saharan African descent). A cluster including Branca (European) and Parda or non-informed (admixed) could be distinguished from both Preta (SubSaharan) and Indígena (Amerindian) groups, and from the Amarela (Asian) ones, which clustered with their original population. These results have implications on cross-population matching and can help in donor searches and population-based recruitment strategies.

East Meets West-Impact of Ethnicity on Donor Match Rates in the Ezer Mizion Bone Marrow Donor Registry.

HLA haplotype frequencies in a volunteer bone marrow donor registry should reflect the frequencies of potential transplant recipients served by that registry, a challenge in a country with diverse subethnicities of immigrants from Eastern and Western cultures, such as Israel. We evaluated the likelihood of finding suitable donors for hypothetical patients drawn from defined subethnicities in the Ezer Mizion Bone Marrow Donor Registry (EM BMDR) from donors both within and outside the registry now and during the coming decade. On average, bioinformatics modeling predicts that, given current donor recruitment trends, 6/6 high-resolution HLA match rates for Israelis, which currently stand at 40% to 55% for most subethnicities, will rise by up to 1% per year over the next decade. Subethnicities with historically lower rates of interethnic admixture are less likely to find matches outside of their designated group but will benefit from expansion of the registry, whereas ethnically directed drives will enhance matching rates for currently underrepresented subethnicities. Donor searches for the same cohort using a large extramural registry was of only slight benefit for most of the 19 EM BMDR subethnicities evaluated, confirming that local donor registries that reflect the ethnic diversity of the community being served are best equipped to serve the needs of their respective communities. Contemporary trends of an increasingly multiethnic admixture in Israel may impact the effect of ethnic profiling in assessing future match rates for EM BMDR.

High-resolution HLA A∼B∼DRB1 haplotype frequencies from the Ezer Mizion Bone Marrow Donor Registry in Israel.

We have investigated HLA population alleles and haplotype frequencies for the ethnicities that comprise the contemporary population of Israel, using a large data set from the Ezer Mizion Bone Barrow Donor Registry. We genotyped 275,699 individuals at the HLA-A, -B and -DRB1 loci using HLA genotyping methods. HLA A∼B∼DRB1 haplotype frequencies were estimated from 19 sub-ethnic Jewish populations and other non-Jewish minorities using the maximum likelihood model, which accommodates typing ambiguities. We present overall and sub-ethnicity specific HLA diversity results of the registry, which will help guide a data-driven strategy for future registry expansion.

HLA match likelihoods for Indian patients seeking unrelated donor transplantation grafts: a population-based study.

BACKGROUND: For patients who do not have a suitable human leukocyte antigen (HLA)-matched family donor, unrelated donor registries of adult volunteers and banked umbilical cord blood (UCB) units provide the potential for successful haemopoietic stem-cell transplantation. The size and genetic composition of such registries determines the proportion of patients who will be able to find a suitable match. We aimed to assess the proportion of positive matches for Indian patients. METHODS: Using HLA data from ten existing donor and UCB registries and clinical transplant centres in India, we built population-based genetic models for 14 Indian regions to model Indian registry growth to predict the likelihood of identifying a suitable donor-either an adult donor or UCB-for Indian patients. We computed ranking tables of the top ten haplotypes in each regional group and compared these with four US samples from the National Marrow Donor Program (NMDP) registry. FINDINGS: The mean proportion of individuals who would have a 10/10 adult donor match within India ranged from 14·4% with a registry size of 25 000 to 60·6% with a registry size of 1 000 000. Only when donor registries increased to 250 000 did the match rate within India exceed that found by searching the US-NMDP registry combined with an Indian registry of 25 000 donors. The proportion of matches increased logarithmically with increased registry size (R(2)=0·993). For a UCB registry size of 25 000, 96·4% of individuals would find a 4/6 match; however, only 18·3% would have a 6/6 match. INTERPRETATION: Serial match modelling and follow-up comparisons can identify the relative and progressively greater value of an India-based donor registry and UCB banking network to serve the Indian population. Understanding regional HLA haplotype diversity could guide registry growth and maximise benefit to patients. Similar modelling could guide planning for the needs of other ethnically distinct populations. FUNDING: University of Minnesota and the Indian Council for Medical Research.