Population Haplotype Frequencies Research Articles

HLA Is a Determinant Of The Ethnic Predisposition Of Chronic Lymphocytic Leukemia

IntroductionChronic Lymphocytic Leukemia (CLL) displays remarkable ethnic predisposition for Caucasians with a lower incidence of disease in African Americans and relative sparing of Asian Populations. In addition, CLL displays one of the highest familial predispositions of all hematologic malignancies, yet the genetic basis for these differences is not fully defined. Large scale genome wide association studies (GWAS) of CLL have identified the Human Leukocyte Antigen (HLA) locus and other loci associated with the development of CLL but the contribution of individual HLA alleles has not been extensively examined. The National Marrow Donor Program (NMDP) registry contains a large number of disease cases and donor controls across multiple populations as well as high quality classical HLA typing, making it a powerful source of data for inferring HLA associations for hematologic diseases. Using the NMDP dataset, we report the largest study of the HLA associations for chronic lymphocytic leukemia (CLL) to date. MethodsCases consisted of 2,689 US Caucasian and 298 African-American patients with CLL who underwent HLA typing performed for allogeneic donor search reported to the National Marrow Donor Program (NMDP). 50,000 controls were randomly selected for each population from US individuals who voluntarily enrolled in the NMDP unrelated donor registry. To address ambiguous haplotype phasing inherent to HLA typing, we used population haplotype frequencies to calculate probabilities for genotypes for each possible pair of HLA haplotypes. We then incorporated this typing ambiguity into a statistical model using multiple imputation, allowing us to report high-resolution allele, haplotype, and genotype associations. Patients and controls were compared using multivariate logistic regression using a generalized linear model for the covariates of age, birthdate, gender, and geographical location. To control for multiple testing, we adjusted p-values using False Discovery Rate with a cutoff of 0.05. ResultsWe identified several HLA alleles that are associated with an increased susceptibility to the development of CLL as well as several alleles that are protective in the Caucasian as well as the African American (AA) US population. In Caucasians, A*02:01 (OR = 1.203, p = 0.00053), B*15:01 (OR = 1.264, p = 0.0105), B*38:01 (OR = 1.396, p = 0.0198), DRB1*04:02 (OR = 1.675, p = 0.0006) and DRB1*07:01 (OR = 1.223, p = 0.0006) were predisposing and A*01:01 (OR = 0.849, p = 0.01077), B*08:01 (OR = 0.853, p = 0.0437), B*27:05 (OR = 0.743, p = 0.0356) were protective. For African Americans, we find a different collection of high resolution HLA alleles: B*37:01, B*15:17 and DRB1*09:01 were predisposing to the development of CLL (OR 3.017, 3.089 and 2.144, respectively) with highly statistically significant p-values (0.0344, 0.0344, 0.00057, respectively). At the allele family level, B*44 was found to be protective in both Caucasian (OR = 0.843, p = 0.0115) and AA populations (OR = 0.485, p = 0.0309). The allele family C*07 (OR 0.848, p = 0.0046) was protective in Caucasians while C*04 was protective in AA populations (OR = 0.645, p = 0.0422). Association results also revealed additive effects of individual predisposing alleles within the same haplotype, such as the A*02:01∼C*06:02∼B*13:02∼DRB1*07:01 haplotype, which had a higher odds ratio (OR = 2.2, p = 0.000086) than either A*02:01 or DRB1*07:01. We performed a population risk analysis by applying the currently identified allelic disease associations for Caucasians to the known allele frequency seen in other populations, and determined that HLA allele frequency differences contribute to the lower risk of CLL development for both the AA and Asian populations. ConclusionsWe have identified several HLA associations that confer increased risk of development of CLL in both U.S. Caucasians and African Americans as well as several protective alleles. These results confirm the previously identified association with HLA*02:01 (OR 1.32, Di Bernardo, et al) with highly similar odds ratio. In addition, we identify many HLA allele associations that have not been previously observed due to low statistical power. Differences in HLA predispositions and HLA allele frequency between Caucasian, AA and Asian populations contribute to the difference in incidence of CLL in these populations and may confer inherent biologic differences due to their impact on immune surveillance. Disclosures:Hill:Celgene: Honoraria, Research Funding.

106-P: HLA ALLELE AND HAPLOTYPE FREQUENCIES FOR CHRISTIAN AND MUSLIM ARAB DONORS IN HADASSAH REGISTRY

The Arab Bone Marrow Registry in Hadassah Medical Center collected HLA typings for 18,000 Arab adult donors. We used this information to estimate population allele and haplotype frequencies (HFs). We calculated HLA A ∼ B ∼ DRB1 HFs from 1,541 Christian Arab (CA) and 16,129 Muslim Arab (MA) donors typed by SBT, resolving phase and allelic ambiguity using Expectation Maximization. HFs were estimated at the four-digit level. The most common CA haplotype was A∗33:01 ∼ B∗14:02 ∼ DRB1∗01:02 at a frequency of 1.6%, which is the fifth most common MA haplotype at 0.9%. This haplotype was the second ranked in the US Middle Eastern/North Coast of Africa (MENAFC) at 0.8% and is also a common Jewish haplotype. The most common MA haplotype was A∗01:01 ∼ B∗52:01 ∼ DRB1∗15:02 at 1.4%, which is ranked 41st in CA at 0.04%. This haplotype was ranked 12th in MENAFC at 0.26%. The fourth ranked haplotype for both CA and MA, A∗02:05 ∼ B∗50:01 ∼ DRB1∗07:01, is the most common in Saudi Arabia, Kuwait and Qatar and the fourth most common among Jewish populations. Average homozygosity for CA and MA for HLA-A, -B and -DRB1 was estimated at 6.7% and 6.2% while the top 30 haplotypes had a cumulative frequency of 25% and 19% respectively indicating higher MA genetic diversity. Interestingly, eight DRB1 alleles: 01:02, 03:01, 04:03, 07:01, 11:01, 11:04, 13:03 and 15:02 constituted over 63% of the allele frequencies for both CA and MA while 97% and 30% of patients served by the Arab registry had one or two of these alleles respectively. Additionally, DRB1∗03:01 occurred without the common Caucasian B∗08:01 association in about 85% of CA and MA donors. Clinical data showed that 40% of transplants were for Arab patients while others were for patients worldwide. Comparing CA and MA to other published HFs, it is clear that some haplotypes have migrated across populations while others remain isolated, thus adding these donors to the world registry is vital to increase genetic diversity for the benefits of all patients.

Mutant-Bin: Unsupervised Haplotype Estimation of Viral Population Diversity Without Reference Genome

High genetic variability in viral populations plays an important role in disease progression, pathogenesis, and drug resistance. The last few years has seen significant progress in the development of methods for reconstruction of viral populations using data from next-generation sequencing technologies. These methods identify the differences between individual haplotypes by mapping the short reads to a reference genome. Much less has been published about resolving the population structure when a reference genome is lacking or is not well-defined, which severely limits the application of these new technologies to resolve virus population structure. We describe a computational framework, called Mutant-Bin, for clustering individual haplotypes in a viral population and determining their prevalence based on a set of deep sequencing reads. The main advantages of our method are that: (i) it enables determination of the population structure and haplotype frequencies when a reference genome is lacking; (ii) the method is unsupervised-the number of haplotypes does not have to be specified in advance; and (iii) it identifies the polymorphic sites that co-occur in a subset of haplotypes and the frequency with which they appear in the viral population. The method was evaluated on simulated reads with sequencing errors and 454 pyrosequencing reads from HIV samples. Our method clustered a high percentage of haplotypes with low false-positive rates, even at low genetic diversity.

Hap-seq: An Optimal Algorithm for Haplotype Phasing with Imputation Using Sequencing Data

Inference of haplotypes, or the sequence of alleles along each chromosome, is a fundamental problem in genetics and is important for many analyses, including admixture mapping, identifying regions of identity by descent, and imputation. Traditionally, haplotypes are inferred from genotype data obtained from microarrays using information on population haplotype frequencies inferred from either a large sample of genotyped individuals or a reference dataset such as the HapMap. Since the availability of large reference datasets, modern approaches for haplotype phasing along these lines are closely related to imputation methods. When applied to data obtained from sequencing studies, a straightforward way to obtain haplotypes is to first infer genotypes from the sequence data and then apply an imputation method. However, this approach does not take into account that alleles on the same sequence read originate from the same chromosome. Haplotype assembly approaches take advantage of this insight and predict haplotypes by assigning the reads to chromosomes in such a way that minimizes the number of conflicts between the reads and the predicted haplotypes. Unfortunately, assembly approaches require very high sequencing coverage and are usually not able to fully reconstruct the haplotypes. In this work, we present a novel approach, Hap-seq, which is simultaneously an imputation and assembly method that combines information from a reference dataset with the information from the reads using a likelihood framework. Our method applies a dynamic programming algorithm to identify the predicted haplotype, which maximizes the joint likelihood of the haplotype with respect to the reference dataset and the haplotype with respect to the observed reads. We show that our method requires only low sequencing coverage and can reconstruct haplotypes containing both common and rare alleles with higher accuracy compared to the state-of-the-art imputation methods.

Clarifying haplotype ambiguity of NAT2 in multi-national cohorts

N-Acetyltransferase 2 (NAT2) is the key enzyme in aromatic amine metabolism. NAT2 genotyping requires a subsequent determination of the haplotype pairs (formerly: alleles) to derive the acetylation status. The chromosomal phase of the single nucleotide polymorphisms (SNPs) is unclear for about 2/3 of the genotypes. We investigated NAT2 genotypes of 1,234 bladder cancer cases and 2,207 controls from Germany, Hungary, Pakistan and Venezuela plus 696 further German cancer cases. We reconstructed NAT2 haplotypes using PHASE v2.1.1. We analysed if the variability of the NAT2 haplotypes affected the haplotype reconstruction. Furthermore, we compared population haplotype frequencies in three Caucasian control cohorts (German, Hungarian, Spanish), in Pakistanis and Venezuelans and the impact on bladder cancer. We conclude that a common haplotype reconstruction is feasible, enhances precision and reliability. Hungarian controls showed the largest intra-ethnic variability whereas the Pakistanis showed a haplotype distribution typical for Caucasians. The main differences could be observed for the slow haplotypes *5B, *6A and *7B. The association of slow NAT2 genotypes with bladder cancer risk was most prominent in the Venezuelan study group.

85-P

Aim The HLA haplotype frequencies for Middle Eastern populations are not well known relative to the rest of the world. At The King Faisal Specialist Hospital and Research Center in Riyadh we have collected HLA typing information for thousands of donors and cord blood units from years of stem-cell and renal transplants with the goal of establishing a stem cell registry in the Kingdom of Saudi Arabia. We aim in this study to use these HLA typings to estimate Saudi population haplotype frequencies and in follow-on work to project HLA match rates for the Saudi population as the registry expands. Methods We calculated HLA A∼C∼B∼DRB1∼DQB1 haplotype frequencies from 2,723 Saudi donors and cord blood units typed by DNA methods, resolving phase and allelic ambiguity using the Expectation Maximization algorithm. Haplotype frequencies were estimated to the allele family level for class I loci and to high resolution at class II loci. Results The most common Saudi HLA haplotype was A∗02∼C∗06∼B∗50∼DRB1∗07:01∼DQB1∗02:02 at a frequency of 4.5%. This haplotype is also the 32nd most common haplotype in the US Caucasian population at a frequency of 0.38%. The 2nd most common Saudi haplotype was A∗02∼C∗07∼B∗07∼DRB1∗15:01∼DQB1∗06:02 at 1.7% frequency, which is also the 4th most common haplotype among US Caucasians, and within Europe is most common in Scandinavia. The 3rd most common Saudi haplotype, A∗26∼C∗07∼B∗08∼DRB1∗03:01∼DQB1∗02:01 at 1.6% frequency, is the 14th most common haplotype in US Asian Pacific Islanders at 0.64%, but is quite rare in US Caucasians (rank 466; 0.0036%). Conclusions his pilot haplotype frequency study and the match rate projection to follow will help to form a data-driven approach to the establishment of a robust stem cell registry of adult donors and cord blood units that will aid the Saudi population in need of transplant. Collection of more detailed ancestry information on Saudi donors has the potential to improve match estimates and ensure all subpopulations are well-served.

93-P

The HLA match rates for the populations served by the Canadian OneMatch registry have not yet been well ascertained. We aimed to use population haplotype frequencies to project HLA match rates for this registry of over 300,000 adult donors and estimate the impact of developing a new cord blood bank. We calculated high-resolution HLA A∼C∼B∼DRB1 haplotype frequencies from 141,405 OneMatch donors typed by DNA methods, resolving both allelic and phase ambiguity using the EM algorithm. Because of population substructure in Aboriginals, we divided the Aboriginal peoples of Western provinces from Eastern provinces. Using frequencies from 13 Canadian sub-populations, we estimated HLA match rates for five years of increasing adult donor registry size and for the establishment and growth of a nascent cord inventory. Matching models considered availability for adult donors and cell dose requirements for cord of 2.5 × 10 7 TNC/kg. Allele-level 8/8 HLA match rates for patients searching for adult donors ranged from 2% for Blacks to 46% for Caucasians. Estimated 7/8 match rates ranged from 12% for Blacks to 86% for Caucasians. We expect that 8/8 and 7/8 match rates will improve by 1-2% per population per year through 2019. Estimated 4/6 match rates for pediatric patients who also search the cord inventory after accrual of 20,000 units ranged from 88% for Blacks to 99% for Caucasians, a substantial marginal benefit. Continued recruitment of adult donors will improve HLA match rates at a steady pace, while development of a cord blood inventory has the potential to close current gaps in stem cell availability, especially for minorities. When analyzing indigenous populations, it is important to consider dividing populations into geographical regions to avoid error in matching models due to population substructure. Recruitment strategy must also be considered in the global context, and we encourage application of similar matching models to all stem cell registries worldwide.

Characterization of the Poly-T Variant in the TOMM40 Gene in Diverse Populations

We previously discovered that a polymorphic, deoxythymidine-homopolymer (poly-T, rs10524523) in intron 6 of the TOMM40 gene is associated with age-of-onset of Alzheimer's disease and with cognitive performance in elderly. Three allele groups were defined for rs10524523, hereafter ‘523’, based on the number of ‘T’-residues: ‘Short’ (S, T≤19), ‘Long’ (L, 20≤T≤29) and ‘Very Long’ (VL, T≥30). Homopolymers, particularly long homopolymers like ‘523’, are difficult to genotype because ‘slippage’ occurs during PCR-amplification. We initially genotyped this locus by PCR-amplification followed by Sanger-sequencing. However, we recognized the need to develop a higher-throughput genotyping method that is also accurate and reliable. Here we describe a new ‘523’ genotyping assay that is simple and inexpensive to perform in a standard molecular genetics laboratory. The assay is based on the detection of differences in PCR-fragment length using capillary electrophoresis. We discuss technical problems, solutions, and the steps taken for validation. We employed the novel assay to investigate the ‘523’ allele frequencies in different ethnicities. Whites and Hispanics have similar frequencies of S/L/VL alleles (0.45/0.11/0.44 and 0.43/0.09/0.48, respectively). In African-Americans, the frequency of the L-allele (0.10) is similar to Whites and Hispanics; however, the S-allele is more prevalent (0.65) and the VL-allele is concomitantly less frequent (0.25). The allele frequencies determined using the new methodology are compared to previous reports for Ghanaian, Japanese, Korean and Han Chinese cohorts. Finally, we studied the linkage pattern between TOMM40-‘523’ and APOE alleles. In Whites and Hispanics, consistent with previous reports, the L is primarily linked to ε4, while the majority of the VL and S are linked to ε3. Interestingly, in African-Americans, Ghanaians and Japanese, there is an increased frequency of the ‘523’S-APOEε4 haplotype. These data may be used as references for ‘523’ allele and ‘523’-APOE haplotype frequencies in diverse populations for the design of research studies and clinical trials.

Homozygosity mapping on a single patient—identification of homozygous regions of recent common ancestry by using population data

Homozygosity mapping has played an important role in detecting recessive mutations using families of consanguineous marriages. However, detection of regions identical and homozygosity by descent (HBD) when family data are not available, or when relationships are unknown, is still a challenge. Making use of population data from high-density SNP genotyping may allow detection of regions HBD from recent common founders in singleton patients without genealogy information. We report a novel algorithm that detects such regions by estimating the population haplotype frequencies (HF) for an entire homozygous region. We also developed a simulation method to evaluate the probability of HBD and linkage to disease for a homozygous region by examining the best regions in unaffected controls from the host population. The method can be applied to diseases of Mendelian inheritance but can also be extended to complex diseases to detect rare founder mutations that affect a very small number of patients using either multiplex families or sporadic cases. Testing of the method on both real cases (singleton affected) and simulated data demonstrated its superb sensitivity and robustness under genetic heterogeneity. Hum Mutat 32:345–353, 2011. © 2011 Wiley-Liss, Inc.

An investigation of 10 Y-STR loci and the detection of specific haplotype frequencies in Turkish population

This study is to survey 10 Y-STR loci in 241 males from Turkey. In this study, the 241 healthy and unrelated males living in different parts of Turkey for at least three generations were included. Genomic DNAs were isolated from peripheral blood samples by standard phenol-chloroform extraction method. 10 Y-STR loci including DYS19, DYS385a/b, DYS388, DYS389I/II, DYS390, DYS391, DYS392, DYS393, and YCAIIa/b were analyzed by using PCR and denaturing PAGE. Allele frequencies, gene diversities and haplotype frequencies were analyzed. Gene diversity per locus varied from 0.5788 (DYS388) to 0.8903 (DYS385a/b). The numbers of haplotypes in minHt recommended by YCC and Ht10 have been 208 and 186, respectively. When our minHt haplotypes frequencies compared with the other seven populations, we have found statistically significant differences between our results and other populations (P 0.05). We suggest that an alternative haplotype designated as aHt maybe alternative to minHt in respect of its Y-STR content with the highest gene diversity value. The aHt haplotype has found a higher discriminatory potential than minHt haplotype with a better Pd combined value (0.9999936 vs 0.9999836) and has higher average gene diversity per locus (0.7834 vs 0.7518) in Turkish population. aHt haplotype can be proposed as an alternative to minHt in paternity testing and forensic medicine applications involving Turkish male population. This study has also provided additional information to the framework of variation involving 10 Y-STR loci as well as a further contribution to the Y-STR database for Turkish male population.

HLA-A, -B, -C, -DQB1, and -DRB1,3,4,5 allele and haplotype frequencies in the Costa Rica Central Valley Population and its relationship to worldwide populations

The human leukocyte antigen (HLA) system is the most polymorphic in humans. Its allele, genotype, and haplotype frequencies vary significantly among different populations. Molecular typing data on HLA are necessary for the development of stem cell donor registries, cord blood banks, HLA–disease association studies, and anthropology studies. The Costa Rica Central Valley Population (CCVP) is the major population in this country. No previous study has characterized HLA frequencies in this population. Allele group and haplotype frequencies of HLA genes in the CCVP were determined by means of molecular typing in a sample of 130 unrelated blood donors from one of the country's major hospitals. A comparison between these frequencies and those of 126 populations worldwide was also carried out. A minimum variance dendrogram based on squared Euclidean distances was constructed to assess the relationship between the CCVP sample and populations from all over the world. Allele group and haplotype frequencies observed in this study are consistent with a profile of a dynamic and diverse population, with a hybrid ethnic origin, predominantly Caucasian-Amerindian. Results showed that populations genetically closest to the CCVP are a Mestizo urban population from Venezuela, and another one from Guadalajara, Mexico.

Delineation of discrete population segments of shortnose sturgeon Acipenser brevirostrum based on mitochondrial DNA control region sequence analysis

Shortnose sturgeon Acipenser brevirostrum is federally listed as ‘‘an endangered species threatened with extinction’’ in the U.S. but its listing status is currently under review. As part of this process, the U.S. National Marine Fisheries Service will determine if shortnose sturgeon are divided into Distinct Population Segments (DPS) across its distribution. In this regard, we sought to determine if shortnose sturgeon occur in genetically “discrete population segments,” and if so, the boundaries of each. We used mitochondrial DNA (mtDNA) control region sequence analysis to assess the genetic discreteness of 14 of 19 river populations that were recommended as DPS in the 1998 Final Recovery Plan for Shortnose Sturgeon. Nine of the 14 proposed DPS proved significantly discrete (P < 0.05 after Bonferoni correction) from both of their bracketing populations, the exceptions being those in the Penobscot River, Chesapeake Bay, Cooper River, and Ogeechee River (our sample from the Cape Fear River was insufficient to statistically analyze). Haplotype frequencies in the newly “rediscovered” Penobscot River collection were almost identical to those in the proximal Kennebec River system. Genetic data in combination with tagging results suggest that shortnose sturgeon in the Penobscot River are probably migrants from the Kennebec. Likewise, shortnose sturgeon found today within the Chesapeake Bay appear to be migrants from the Delaware River. While haplotype frequencies in the remnant Santee River population in Lake Marion differed significantly from those in nearby Winyah Bay, they did not differ significantly from those in the Cooper River. This suggests that the Cooper River harbors descendants of the Santee River population that are unable to access their historical spawning locales. The Ogeechee River collection was not genetically distinct from that in the nearby Savannah River, suggesting that it may host descendants of hatchery-reared individuals of Savannah River ancestry. Our genetic results indicate that most, but not all, rivers with shortnose sturgeon host genetically discrete populations, constituting important information in the consideration of DPS designations. However, shortnose sturgeon migrations through coastal waters to proximal rivers and release of hatchery-reared fish may confound results from genetic studies such as ours and lead to the possible misidentification of discrete population segments.

Population-specific variation in haplotype composition and heterozygosity at the POLB locus

DNA polymerase beta plays a central role in base excision repair (BER), which removes large numbers of endogenous DNA lesions from each cell on a daily basis. Little is currently known about germline polymorphisms within the POLB locus, making it difficult to study the association of variants at this locus with human diseases such as cancer. Yet, approximately thirty percent of human tumor types show variants of DNA polymerase beta. We have assessed the global frequency distributions of coding and common non-coding SNPs in and flanking the POLB gene for a total of 14 sites typed in approximately 2400 individuals from anthropologically defined human populations worldwide. We have found a marked difference between haplotype frequencies in African populations and in non-African populations.

Analysis of Allele and Haplotype Diversity Across 25 Genomic Regions in Three Eastern European Populations

Objective: Individual population history is the main reason for the variability of linkage disequilibrium (LD) patterns and haplotype frequencies among populations. Such diversity may influence the transferability of tag SNPs from one population to another. Our goal was to compare patterns of pairwise LD and allele and haplotype frequencies in Estonian and Russian populations, to estimate the genetic variation between populations and assess the potential transferability of tag SNPs. Methods: 452 SNPs from 25 unlinked genomic regions on 12 chromosomes were genotyped in 140 Estonians and 207 Russians from Northern and Western regions of the European area of Russia. Results: The allele frequency distributions were highly consistent between populations (R > 0.90 for all pairwise comparisons). The overall frequency variation among populations was low (F_ST = 0.0054). The number of SNPs with high-range F_ST values (0.02–0.09) was most prominent for the MC5R genomic region. Haplotype heterogeneity among populations was low (F_ST values ranged within 0.00–0.01, with the exception of haploblocks in the ADIPOR2 and MC5R regions). The interpopulation proximity was also evaluated using haplotype diversity. Conclusion: Our data showed a high concordance between the populations studied, which may be considered as the result of their historical formation on a cognate genetic basis.

Estimating population haplotype frequencies from pooled DNA samples using PHASE algorithm

Recent studies show that the PHASE algorithm is a state-of-the-art method for population-based haplotyping from individually genotyped data. We present a modified version of PHASE for estimating population haplotype frequencies from pooled DNA data. The algorithm is compared with (i) a maximum likelihood estimation under the multinomial model and (ii) a deterministic greedy algorithm, on both simulated and real data sets (HapMap data). Our results suggest that the PHASE algorithm is a method of choice also on pooled DNA data. The main reason for improvement over the other approaches is assumed to be the same as with individually genotyped data: the biologically motivated model of PHASE takes into account correlated genealogical histories of the haplotypes by modelling mutations and recombinations. The important questions of efficiency of DNA pooling as well as influence of the pool size on the accuracy of the estimates are also considered. Our results are in line with the earlier findings in that the pool size should be relatively small, only 2-5 individuals in our examples, in order to provide reliable estimates of population haplotype frequencies.

Estimation of graphical models whose conditional independence graphs are interval graphs and its application to modelling linkage disequilibrium

Estimation of graphical models whose conditional independence graph comes from the general class of decomposable graphs is compared with estimation under the more restrictive assumption that the graphs are interval graphs. This restriction is shown to improve the mixing of the Markov chain Monte Carlo search to find an optimal model with little effect on the haplotype frequencies implied by the estimates. A further restriction requiring intervals to cover specified points is also considered and shown to be appropriate for modelling associations between alleles at genetic loci. As well as usefully describing the patterns of associations, these estimates can also be used to model population haplotype frequencies in statistical gene mapping methods such as linkage analysis and association studies.

Comparison of SLCO1B1 sequence variability among German, Turkish, and African populations

OATP1B1 is one of the key hepatocellular uptake transporters providing extraction of diverse compounds, including bile acids, xenobiotics, and a variety of drugs, from portal venous blood into the liver. Polymorphisms of the SLCO1B1 gene have been demonstrated to influence in vitro transport function and the pharmacokinetic profile of compounds. The goal of our study was the comparison of SLCO1B1 gene sequence variability in three ethnic groups as a basis for future genetic association studies. Eighteen exonic SLCO1B1 single nucleotide polymorphisms (SNPs) were genotyped by PCR and RFLP analysis in 300 German, 94 Turkish, and 115 African subjects. Calculation of pairwise linkage disequilibrium and estimation of population haplotype frequencies were carried out, and haplotype block structure was determined. Only eight genotyped SNPs (c.388A>G, c.411G>A, c.463C>A, c.521T>C, c.571C>T, c.597C>T, c.1463G>>C, c.1929A>C) were found in at least one of our German, Turkish, or African samples. A total of 12 haplotypes with a frequency >or=1% in at least one of the three populations could be inferred. Between the Caucasian and African samples, significant differences in sequence variability were observed leading to a different haplotype profile in these populations. Our results demonstrate a high sequence variability of OATP1B1 within different popuations. In the future, distinct haplotypes should be taken into account when studying the effect of OATP1B1 on drugs in different populations.

HaploPool: improving haplotype frequency estimation through DNA pools and phylogenetic modeling

The search for genetic variants that are linked to complex diseases such as cancer, Parkinson's;, or Alzheimer's; disease, may lead to better treatments. Since haplotypes can serve as proxies for hidden variants, one method of finding the linked variants is to look for case-control associations between the haplotypes and disease. Finding these associations requires a high-quality estimation of the haplotype frequencies in the population. To this end, we present, HaploPool, a method of estimating haplotype frequencies from blocks of consecutive SNPs. HaploPool leverages the efficiency of DNA pools and estimates the population haplotype frequencies from pools of disjoint sets, each containing two or three unrelated individuals. We study the trade-off between pooling efficiency and accuracy of haplotype frequency estimates. For a fixed genotyping budget, HaploPool performs favorably on pools of two individuals as compared with a state-of-the-art non-pooled phasing method, PHASE. Of independent interest, HaploPool can be used to phase non-pooled genotype data with an accuracy approaching that of PHASE. We compared our algorithm to three programs that estimate haplotype frequencies from pooled data. HaploPool is an order of magnitude more efficient (at least six times faster), and considerably more accurate than previous methods. In contrast to previous methods, HaploPool performs well with missing data, genotyping errors and long haplotype blocks (of between 5 and 25 SNPs).

The distribution of major histocompatibility complex class I polymorphic Alu insertions and their associations with HLA alleles in a Chinese population from Malaysia

The frequency and association of polymorphic Alu insertions (POALINs) with human leucocyte antigen (HLA) class I genes within the class I genomic region of the major histocompatibility complex (MHC) have been reported previously for three populations: the Australian Caucasian, Japanese and north-eastern Thai populations. Here, we report on the individual insertion frequency of the five POALINs within the MHC class I region, their HLA-A and HLA-B associations, the POALIN haplotype frequencies and the HLA-A/POALIN four-loci haplotype frequencies in the Malaysian Chinese population. The phylogenetic relationship of the four populations based on the five POALIN allele frequencies was also examined. In the Malaysian Chinese population, the POALIN AluyHG was present at the highest frequency (0.560), followed by AluyHJ (0.300), AluyMICB (0.170), AluyTF (0.040) and AluyHF (0.030). The most frequent five-loci POALIN haplotype of the 16 inferred haplotypes was the AluyHG single insertion haplotype at a frequency of 0.489. Strong associations were present between AluyHJ and HLA-A24, HLA-A33 and HLA-A11 and between AluyHG and HLA-A2, HLA-A24 and HLA-A11, and these were reflected by the inferred haplotype frequencies constructed from the combination of the HLA-A locus and the AluyHG, AluyHJ and AluyHF loci. The strongest association of AluyMICB was with the HLA-B54 allele (five of five), whereas the associations with the other 17 HLA-B alleles were weak, moderate or undetermined. Phylogenetic analysis of the five POALIN allele frequencies places the Malaysian Chinese closest to the Japanese and north-eastern Thai populations in the same cluster and separate to the Australian Caucasian population. The MHC POALINs are confirmed in this study to be informative genetic markers in lineage (haplotype) analysis, population genetics and evolutionary relationships, especially in studying the MHC genomic region.

Family‐based association study of neuregulin‐1 gene and psychosis in a Spanish sample

Neuregulin 1 (NRG1) is one of the most exciting candidate genes for schizophrenia since its first association with the disorder in an Icelandic population. Since then, many studies have analyzed allele and haplotype frequencies in European and Asian populations in cases and controls yielding varying results. We investigated the association of NRG1 with psychosis in a total sample set of 575 individuals from 151 Spanish nuclear families. We tested eight SNPs across 1.2 Mb along NRG1 including regions previously associated to schizophrenia in association studies. After correction for multiple testing, the TDT analysis for each marker did not show a significant over-transmission of alleles from the parents to the affected offspring for any of the markers (P > 0.05). The haplotypic analysis with TRANSMIT and PDT did not show preferential transmission for any of the haplotypes analyzed in our sample. These results do not seem to suggest that the investigated NRG1 markers play a role in schizophrenia in the Spanish population, although the finding of a trend for association with one SNP in the 3'of the gene warrants further investigation.