Publications by authors named "Gorka Alkorta-Aranburu"

23 Publications

  • Page 1 of 1

Next-generation sequencing of bile cell-free DNA for the early detection of patients with malignant biliary strictures.

Gut 2021 Jul 20. Epub 2021 Jul 20.

Navarra Institute for Health Research, IdiSNA, Pamplona, Spain.

Objective: Despite significant progresses in imaging and pathological evaluation, early differentiation between benign and malignant biliary strictures remains challenging. Endoscopic retrograde cholangiopancreatography (ERCP) is used to investigate biliary strictures, enabling the collection of bile. We tested the diagnostic potential of next-generation sequencing (NGS) mutational analysis of bile cell-free DNA (cfDNA).

Design: A prospective cohort of patients with suspicious biliary strictures (n=68) was studied. The performance of initial pathological diagnosis was compared with that of the mutational analysis of bile cfDNA collected at the time of first ERCP using an NGS panel open to clinical laboratory implementation, the Oncomine Pan-Cancer Cell-Free assay.

Results: An initial pathological diagnosis classified these strictures as of benign (n=26), indeterminate (n=9) or malignant (n=33) origin. Sensitivity and specificity of this diagnosis were 60% and 100%, respectively, as on follow-up 14 of the 26 and eight of the nine initially benign or indeterminate strictures resulted malignant. Sensitivity and specificity for malignancy of our NGS assay, herein named Bilemut, were 96.4% and 69.2%, respectively. Importantly, one of the four Bilemut false positives developed pancreatic cancer after extended follow-up. Remarkably, the sensitivity for malignancy of Bilemut was 100% in patients with an initial diagnosis of benign or indeterminate strictures. Analysis of 30 paired bile and tissue samples also demonstrated the superior performance of Bilemut.

Conclusion: Implementation of Bilemut at the initial diagnostic stage for biliary strictures can significantly improve detection of malignancy, reduce delays in the clinical management of patients and assist in selecting patients for targeted therapies.
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http://dx.doi.org/10.1136/gutjnl-2021-325178DOI Listing
July 2021

Machine Learning-Based Approach Highlights the Use of a Genomic Variant Profile for Precision Medicine in Ovarian Failure.

J Pers Med 2021 Jun 27;11(7). Epub 2021 Jun 27.

IVI Foundation-Instituto de Investigación Sanitaria La Fe, Av. Fernando Abril Martorell 106, Torre A, Planta 1ª, 46026 Valencia, Spain.

Ovarian failure (OF) is a common cause of infertility usually diagnosed as idiopathic, with genetic causes accounting for 10-25% of cases. Whole-exome sequencing (WES) may enable identifying contributing genes and variant profiles to stratify the population into subtypes of OF. This study sought to identify a blood-based gene variant profile using accumulation of rare variants to promote precision medicine in fertility preservation programs. A case-control ( = 118, = 32, respectively) WES study was performed in which only non-synonymous rare variants <5% minor allele frequency (MAF; in the IGSR) and coverage ≥ 100× were considered. A profile of 66 variants of uncertain significance was used for training an unsupervised machine learning model to separate cases from controls (97.2% sensitivity, 99.2% specificity) and stratify the population into two subtypes of OF (A and B) (93.31% sensitivity, 96.67% specificity). Model testing within the IGSR female population predicted 0.5% of women as subtype A and 2.4% as subtype B. This is the first study linking OF to the accumulation of rare variants and generates a new potential taxonomy supporting application of this approach for precision medicine in fertility preservation.
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http://dx.doi.org/10.3390/jpm11070609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305607PMC
June 2021

Performance comparison of two next-generation sequencing panels to detect actionable mutations in cell-free DNA in cancer patients.

Clin Chem Lab Med 2020 07;58(8):1341-1348

Service of Biochemistry, Clínica Universidad de Navarra, Pamplona, Spain.

Background Genomic alterations studies in cell-free DNA (cfDNA) have increasing clinical use in oncology. Next-generation sequencing (NGS) technology provides the most complete mutational analysis, but nowadays limited data are available related to the comparison of results reported by different platforms. Here we compare two NGS panels for cfDNA: Oncomine™ Pan-Cancer Cell-Free Assay (Thermo Fisher Scientific), suitable for clinical laboratories, and Guardant360® (GuardantHealth), with more genes targeted but only available in an outsourcing laboratory. Methods Peripheral blood was obtained from 16 advanced cancer patients in which Guardant360® (G360) was requested as part of their clinical assistance. Blood samples were sent to be analyzed with G360 panel, and an additional blood sample was drawn to obtain and analyze cfDNA with Oncomine™ Pan-Cancer (OM) panel in an Ion GeneStudio S5™ System. Results cfDNA analysis globally rendered 101 mutations. Regarding the 55/101 mutations claimed to be included by manufacturers in both panels, 17 mutations were reported only by G360, 10 only by OM and 28 by both. In those coincident cases, there was a high correlation between the variant allele fractions (VAFs) calculated with each panel (r = 0.979, p < 0.01). Regarding the six actionable mutations with an FDA-approved therapy reported by G360, one was missed with OM. Also, 12 mutations with clinical trials available were reported by G360 but not by OM. Conclusions In summary, G360 and OM can produce different mutational profile in the same sample, even in genes included in both panels, which is especially important if these mutations are potentially druggable.
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http://dx.doi.org/10.1515/cclm-2019-1267DOI Listing
July 2020

The Dynamic Use of Mutation Analysis in Cell-Free DNA as a Follow-Up Biomarker during Different Treatment Lines in Non-Small-Cell Lung Cancer Patients.

Dis Markers 2019 23;2019:7954921. Epub 2019 Jan 23.

Service of Biochemistry, Clínica Universidad de Navarra, Av. Pio XII 36 Pamplona 31008, Spain.

Epidermal growth factor receptor () mutational testing in advanced non-small-cell lung cancer (NSCLC) is usually performed in tumor tissue, although cfDNA (cell-free DNA) could be an alternative. We evaluated mutations in cfDNA as a complementary tool in patients, who had already known mutations in tumor tissue and were treated with either EGFR-tyrosine kinase inhibitors (TKIs) or chemotherapy. We obtained plasma samples from 21 advanced NSCLC patients with known tumor mutations, before and during therapy with EGFR-TKIs and/or chemotherapy. cfDNA was isolated and mutations were analyzed with the multiple targeted cobas EGFR Mutation Test v2. mutations were detected at baseline in cfDNA from 57% of patients. The semiquantitative index (SQI) significantly decreased from the baseline (median = 11, IQR = 9.5-13) to the best response (median = 0, IQR = 0-0, < 0.01), followed by a significant increase at progression (median = 11, IQR = 11-15, < 0.01) in patients treated with either EGFR-TKIs or chemotherapy. The SQI obtained with the cobas EGFR Mutation Test v2 did not correlate with the concentration in copies/mL determined by droplet digital PCR. Resistance mutation p.T790M was observed at progression in patients with either type of treatment. In conclusion, cfDNA multiple targeted mutation analysis is useful for treatment monitoring in tissue of -positive NSCLC patients independently of the drug received.
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http://dx.doi.org/10.1155/2019/7954921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6364099PMC
June 2019

Reprogramming human T cell function and specificity with non-viral genome targeting.

Nature 2018 07 11;559(7714):405-409. Epub 2018 Jul 11.

HIV Dynamics and Replication Program, Vector Design and Replication Section, National Cancer Institute, Frederick, MD, USA.

Decades of work have aimed to genetically reprogram T cells for therapeutic purposes using recombinant viral vectors, which do not target transgenes to specific genomic sites. The need for viral vectors has slowed down research and clinical use as their manufacturing and testing is lengthy and expensive. Genome editing brought the promise of specific and efficient insertion of large transgenes into target cells using homology-directed repair. Here we developed a CRISPR-Cas9 genome-targeting system that does not require viral vectors, allowing rapid and efficient insertion of large DNA sequences (greater than one kilobase) at specific sites in the genomes of primary human T cells, while preserving cell viability and function. This permits individual or multiplexed modification of endogenous genes. First, we applied this strategy to correct a pathogenic IL2RA mutation in cells from patients with monogenic autoimmune disease, and demonstrate improved signalling function. Second, we replaced the endogenous T cell receptor (TCR) locus with a new TCR that redirected T cells to a cancer antigen. The resulting TCR-engineered T cells specifically recognized tumour antigens and mounted productive anti-tumour cell responses in vitro and in vivo. Together, these studies provide preclinical evidence that non-viral genome targeting can enable rapid and flexible experimental manipulation and therapeutic engineering of primary human immune cells.
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http://dx.doi.org/10.1038/s41586-018-0326-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6239417PMC
July 2018

Does arterial hypertension influence the onset of Huntington's disease?

PLoS One 2018 23;13(5):e0197975. Epub 2018 May 23.

Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV/EHU), Leioa, Spain.

Huntington's disease (HD) age of onset (AO) is mainly determined by the length of the CAG repeat expansion in the huntingtin gene. The remaining AO variability has been attributed to other little-known factors. A factor that has been associated with other neurodegenerative diseases is arterial hypertension (AHT). The aim of this study is to evaluate the contribution of AHT to the AO of HD. We used data from a cohort of 630 European HD patients with adult onset collected by the REGISTRY project of the European Huntington's Disease Network. Multiple linear regression and ANOVA, controlling for the CAG repeat number of the expanded allele (CAGexp) of each patient, were performed to assess the association between the AHT condition and the AO of the motor symptoms (mAO). The results showed a significant association between AHT and mAO, especially when we only considered the patients diagnosed with AHT prior to manifesting any HD signs (pre-HD AHT). Remarkably, despite the low number of cases, those patients developed motor symptoms 5-8 years later than normotensive patients in the most frequent CAGexp range (40-44). AHT is an age-related condition and consequently, the age of the patient at the time of data collection could be a confounder variable. However, given that most pre-HD AHT patients included in our study had started treatment with antihypertensive drugs prior to the onset of HD, and that antihypertensive drugs have been suggested to confer a neuroprotective effect in other neurodegenerative diseases, raises the interest in elucidating the impact of AHT and/or AHT treatment in HD age of onset in further studies. A confirmation of our results in a larger sample set would open the possibility to significantly improve HD management.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0197975PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5965871PMC
November 2018

Pancreatic Histopathology of Human Monogenic Diabetes Due to Causal Variants in KCNJ11, HNF1A, GATA6, and LMNA.

J Clin Endocrinol Metab 2018 01;103(1):35-45

Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, The University of Chicago, Chicago, Illinois.

Context: Monogenic diabetes is thought to account for 2% of all diabetes cases, but most patients receive misdiagnoses of type 1 or type 2 diabetes. To date, little is known about the histopathological features of pancreata from patients with monogenic diabetes.

Objective: Retrospective study of the JDRF Network for Pancreatic Organ Donors with Diabetes biorepository to identify possible cases of monogenic diabetes and to compare effects of genetic variants on pancreas histology.

Methods: We selected cases of diabetes for genetic testing on the basis of criteria that included young age at diagnosis, low body mass index, negative autoantibody status, and/or detectable C-peptide level. Samples underwent next-generation-targeted sequencing of 140 diabetes/diabetes-related genes. Pancreas weight and histopathology were reviewed.

Results: Forty-one of 140 cases of diabetes met the clinical inclusion criteria, with 38 DNA samples available. Genetic variants of probable clinical significance were found in four cases: one each in KCNJ11, HNF1A, GATA6, and LMNA. The KCNJ11 and HNF1A samples had significantly decreased pancreas weight and insulin mass similar to that of type 1 diabetes but had no insulitis. The GATA6 sample had severe pancreatic atrophy but with abundant β cells and severe amyloidosis similar to type 2 diabetes. The LMNA sample had preserved pancreas weight and insulin mass but abnormal islet architecture and exocrine fatty infiltrates.

Conclusions: Four cases of diabetes had putative causal variants in monogenic diabetes genes. This study provides further insight into the heterogeneous nature of monogenic diabetes cases that exhibited clinical and pathophysiological features that overlap with type 1/type 2 diabetes.
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http://dx.doi.org/10.1210/jc.2017-01159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5761488PMC
January 2018

Rare form of autosomal dominant familial Cornelia de Lange syndrome due to a novel duplication in SMC3.

Clin Case Rep 2017 08 28;5(8):1277-1283. Epub 2017 Jun 28.

Department of Pediatrics Division of Medical Genetics Children's Hospital of Pittsburgh of UPMC Pittsburgh Pennsylvania.

Clinical features are variable in patients with Cornelia de Lange syndrome (CdLS). Milder forms exist with structural maintenance of chromosomes 3 (SMC3) mutations. Inherited milder forms of CdLS are uncommon and may be missed if genetic testing is limited to Nipped-B-like protein (NIPBL) and SMC1A. Parental studies should be pursued if there is a history of learning disabilities and/or dysmorphic features.
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http://dx.doi.org/10.1002/ccr3.1010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538066PMC
August 2017

Improved molecular diagnosis of patients with neonatal diabetes using a combined next-generation sequencing and MS-MLPA approach.

J Pediatr Endocrinol Metab 2016 May;29(5):523-31

Background: We evaluated a methylation-specific multiplex-ligation-dependent probe amplification (MS-MLPA) assay for the molecular diagnosis of transient neonatal diabetes mellitus (TNDM) caused by 6q24 abnormalities and assessed the clinical utility of using this assay in combination with next generation sequencing (NGS) analysis for diagnosing patients with neonatal diabetes (NDM).

Methods: We performed MS-MLPA in 18 control samples and 42 retrospective NDM cases with normal bi-parental inheritance of chromosome 6. Next, we evaluated 22 prospective patients by combining NGS analysis of 11 NDM genes and the MS-MLPA assay.

Results: 6q24 aberrations were identified in all controls and in 19% of patients with normal bi-parental inheritance of chromosome 6. The MS-MLPA/NGS combined approach identified a genetic cause in ~64% of patients with NDM of unknown etiology.

Conclusions: MS-MLPA is a reliable method to identify all known 6q24 abnormalities and comprehensive testing of all causes reveals a causal mutation in ~64% of patients.
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http://dx.doi.org/10.1515/jpem-2015-0341DOI Listing
May 2016

Olfactory Dysfunction in Older Adults is Associated with Feelings of Depression and Loneliness.

Chem Senses 2016 05 24;41(4):293-9. Epub 2016 Jan 24.

Section of Otolaryngology-Head and Neck Surgery, The University of Chicago, 5841 S. Maryland Ave MC 1035, Chicago, IL 60637, USA, Center on the Demography and Economics of Aging, The University of Chicago, 1155 E. 60th Street, Suite 341, Chicago, IL 60637, USA

Olfactory dysfunction is a common complaint among physician visits. Olfactory loss affects quality of life and impairs function and activities of daily living. The purpose of our study was to assess the degree of odor identification associated with mental health. Olfactory function was measured using the brief smell identification test. Depressive symptoms were measured by the Center for Epidemiologic Studies Depression scale. Loneliness was assessed by the de Jong-Gierveld Loneliness Scale. Cognition was measured by a battery of 19 cognitive tests. The frequency of olfactory dysfunction in our study was ~40%. Older subjects had worse olfactory performance, as previously found. More loneliness was associated with worse odor identification. Similarly, symptoms of depression were associated with worse olfaction (among men). Although better global cognitive function was strongly associated with better odor identification, after controlling for multiple factors, the associations with depression and loneliness were unchanged. Clinicians should assess these mental health conditions when treating older patients who present with olfactory deficits.
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http://dx.doi.org/10.1093/chemse/bjv088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5006107PMC
May 2016

Genome-wide Meta-analysis on the Sense of Smell Among US Older Adults.

Medicine (Baltimore) 2015 Nov;94(47):e1892

From the Epidemiology Branch (JD, ZX, SL, HC) and Biostatistics Branch (LN), National Institute of Environmental Health Sciences, Research Triangle Park, NC; Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL (JY, RSW, LY, DAB); California Pacific Medical Center Research Institute, San Francisco, CA (GT, NP, SC); Department of Epidemiology, University of North Carolina Gillings School of Global Public Health, Chapel Hill, NC (NF); Department of Human Genetics, University of Chicago, Chicago, IL (GA-A); Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN (AA); Institute of Molecular Medicine and Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX (MF); Pennsylvania State University-Milton S. Hershey Medical Center, Hershey, PA (XH); Sticht Center on Aging (SK) and Division of Public Health Sciences (YL), Wake Forest School of Medicine, Winston-Salem, NC; Program in Translational Neuro Psychiatric Genomics, Departments of Neurology and Psychiatry, Institute for the Neurosciences, Brigham and Women's Hospital; Harvard Medical School; Program in Medical and Population Genetics, Broad Institute, Boston, MA (PLD); Laboratory of Neurogenetics (ABS) and Laboratory of Epidemiology, Demography, and Biometry (TH), National Institute on Aging, Bethesda, MD; Division of Geriatrics, Department of Medicine, University of Mississippi Medical Center, Jackson, MS (THM); Section of Otolaryngology-Head and Neck Surgery, Department of Surgery, The University of Chicago Medicine and Biological Sciences, Chicago, IL (JMP); Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA (JY, LY, DAB); and Departments of Neurological Sciences and Behavioral Sciences, Rush University Medical Center, Chicago, IL, USA (RSW).

Olfactory dysfunction is common among older adults and affects their safety, nutrition, quality of life, and mortality. More importantly, the decreased sense of smell is an early symptom of neurodegenerative diseases such as Parkinson disease (PD) and Alzheimer disease. However, the genetic determinants for the sense of smell have been poorly investigated. We here performed the first genome-wide meta-analysis on the sense of smell among 6252 US older adults of European descent from the Atherosclerosis Risk in Communities (ARIC) study, the Health, Aging, and Body Composition (Health ABC) study, and the Religious Orders Study and the Rush Memory and Aging Project (ROS/MAP). Genome-wide association study analysis was performed first by individual cohorts and then meta-analyzed using fixed-effect models with inverse variance weights. Although no SNPs reached genome-wide statistical significance, we identified 13 loci with suggestive evidence for an association with the sense of smell (Pmeta < 1 × 10). Of these, 2 SNPs at chromosome 17q21.31 (rs199443 in NSF, P = 3.02 × 10; and rs2732614 in KIAA1267-LRRC37A, P = 6.65 × 10) exhibited cis effects on the expression of microtubule-associated protein tau (MAPT, 17q21.31) in 447 frontal-cortex samples obtained postmortem and profiled by RNA-seq (P < 1 × 10). Gene-based and pathway-enrichment analyses further implicated MAPT in regulating the sense of smell in older adults. Similar results were obtained after excluding participants who reported a physician-diagnosed PD or use of PD medications. In conclusion, we provide preliminary evidence that the MAPT locus may play a role in regulating the sense of smell in older adults and therefore offer a potential genetic link between poor sense of smell and major neurodegenerative diseases.
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http://dx.doi.org/10.1097/MD.0000000000001892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5058953PMC
November 2015

Estimating the Ages of Selection Signals from Different Epochs in Human History.

Mol Biol Evol 2016 Mar 5;33(3):657-69. Epub 2015 Nov 5.

Department of Human Genetics, University of Chicago

Genetic variation harbors signatures of natural selection driven by selective pressures that are often unknown. Estimating the ages of selection signals may allow reconstructing the history of environmental changes that shaped human phenotypes and diseases. We have developed an approximate Bayesian computation (ABC) approach to estimate allele ages under a model of selection on new mutations and under demographic models appropriate for human populations. We have applied it to two resequencing data sets: An ultra-high depth data set from a relatively small sample of unrelated individuals and a lower depth data set in a larger sample with transmission information. In addition to evaluating the accuracy of our method based on simulations, for each SNP, we assessed the consistency between the posterior probabilities estimated by the ABC approach and the ancient DNA record, finding good agreement between the two types of data and methods. Applying this ABC approach to data for eight single nucleotide polymorphisms (SNPs), we were able to rule out an onset of selection prior to the dispersal out-of-Africa for three of them and more recent than the spread of agriculture for an additional three SNPs.
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http://dx.doi.org/10.1093/molbev/msv256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5009997PMC
March 2016

Exploring Genetic Factors Involved in Huntington Disease Age of Onset: E2F2 as a New Potential Modifier Gene.

PLoS One 2015 6;10(7):e0131573. Epub 2015 Jul 6.

Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV/EHU), Leioa, Spain.

Age of onset (AO) of Huntington disease (HD) is mainly determined by the length of the CAG repeat expansion (CAGexp) in exon 1 of the HTT gene. Additional genetic variation has been suggested to contribute to AO, although the mechanism by which it could affect AO is presently unknown. The aim of this study is to explore the contribution of candidate genetic factors to HD AO in order to gain insight into the pathogenic mechanisms underlying this disorder. For that purpose, two AO definitions were used: the earliest age with unequivocal signs of HD (earliest AO or eAO), and the first motor symptoms age (motor AO or mAO). Multiple linear regression analyses were performed between genetic variation within 20 candidate genes and eAO or mAO, using DNA and clinical information of 253 HD patients from REGISTRY project. Gene expression analyses were carried out by RT-qPCR with an independent sample of 35 HD patients from Basque Country Hospitals. We found suggestive association signals between HD eAO and/or mAO and genetic variation within the E2F2, ATF7IP, GRIN2A, GRIN2B, LINC01559, HIP1 and GRIK2 genes. Among them, the most significant was the association between eAO and rs2742976, mapping to the promoter region of E2F2 transcription factor. Furthermore, rs2742976 T allele patient carriers exhibited significantly lower lymphocyte E2F2 gene expression, suggesting a possible implication of E2F2-dependent transcriptional activity in HD pathogenesis. Thus, E2F2 emerges as a new potential HD AO modifier factor.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0131573PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4493078PMC
March 2016

PRIMAL: Fast and accurate pedigree-based imputation from sequence data in a founder population.

PLoS Comput Biol 2015 Mar 3;11(3):e1004139. Epub 2015 Mar 3.

Department of Human Genetics, The University of Chicago, Chicago, Illinois, United States of America; Departments of Medicine, and Statistics, The University of Chicago, Chicago, Illinois, United States of America.

Founder populations and large pedigrees offer many well-known advantages for genetic mapping studies, including cost-efficient study designs. Here, we describe PRIMAL (PedigRee IMputation ALgorithm), a fast and accurate pedigree-based phasing and imputation algorithm for founder populations. PRIMAL incorporates both existing and original ideas, such as a novel indexing strategy of Identity-By-Descent (IBD) segments based on clique graphs. We were able to impute the genomes of 1,317 South Dakota Hutterites, who had genome-wide genotypes for ~300,000 common single nucleotide variants (SNVs), from 98 whole genome sequences. Using a combination of pedigree-based and LD-based imputation, we were able to assign 87% of genotypes with >99% accuracy over the full range of allele frequencies. Using the IBD cliques we were also able to infer the parental origin of 83% of alleles, and genotypes of deceased recent ancestors for whom no genotype information was available. This imputed data set will enable us to better study the relative contribution of rare and common variants on human phenotypes, as well as parental origin effect of disease risk alleles in >1,000 individuals at minimal cost.
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http://dx.doi.org/10.1371/journal.pcbi.1004139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4348507PMC
March 2015

Strong artificial selection in domestic mammals did not result in an increased recombination rate.

Mol Biol Evol 2015 Feb 19;32(2):510-23. Epub 2014 Nov 19.

Conservation and Evolutionary Genetics Group, Estación Biológica de Doñana EBD-CSIC, Sevilla, Spain.

Recombination rates vary in intensity and location at the species, individual, sex and chromosome levels. Despite the fundamental biological importance of this process, the selective forces that operate to shape recombination rate and patterns are unclear. Domestication offers a unique opportunity to study the interplay between recombination and selection. In domesticates, intense selection for particular traits is imposed on small populations over many generations, resulting in organisms that differ, sometimes dramatically, in morphology and physiology from their wild ancestor. Although earlier studies suggested increased recombination rate in domesticates, a formal comparison of recombination rates between domestic mammals and their wild congeners was missing. In order to determine broad-scale recombination rate, we used immunolabeling detection of MLH1 foci as crossover markers in spermatocytes in three pairs of closely related wild and domestic species (dog and wolf, goat and ibex, and sheep and mouflon). In the three pairs, and contrary to previous suggestions, our data show that contemporary recombination rate is higher in the wild species. Subsequently, we inferred recombination breakpoints in sequence data for 16 genomic regions in dogs and wolves, each containing a locus associated with a dog phenotype potentially under selection during domestication. No difference in the number and distribution of recombination breakpoints was found between dogs and wolves. We conclude that our data indicate that strong directional selection did not result in changes in recombination in domestic mammals, and that both upper and lower bounds for crossover rates may be tightly regulated.
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http://dx.doi.org/10.1093/molbev/msu322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4298180PMC
February 2015

Admixture facilitates genetic adaptations to high altitude in Tibet.

Nat Commun 2014 ;5:3281

Department of Human Genetics, University of Chicago, Chicago, Illinois 60637, USA.

Admixture is recognized as a widespread feature of human populations, renewing interest in the possibility that genetic exchange can facilitate adaptations to new environments. Studies of Tibetans revealed candidates for high-altitude adaptations in the EGLN1 and EPAS1 genes, associated with lower haemoglobin concentration. However, the history of these variants or that of Tibetans remains poorly understood. Here we analyse genotype data for the Nepalese Sherpa, and find that Tibetans are a mixture of ancestral populations related to the Sherpa and Han Chinese. EGLN1 and EPAS1 genes show a striking enrichment of high-altitude ancestry in the Tibetan genome, indicating that migrants from low altitude acquired adaptive alleles from the highlanders. Accordingly, the Sherpa and Tibetans share adaptive haemoglobin traits. This admixture-mediated adaptation shares important features with adaptive introgression. Therefore, we identify a novel mechanism, beyond selection on new mutations or on standing variation, through which populations can adapt to local environments.
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http://dx.doi.org/10.1038/ncomms4281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4643256PMC
November 2015

The genetic architecture of adaptations to high altitude in Ethiopia.

PLoS Genet 2012 6;8(12):e1003110. Epub 2012 Dec 6.

Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America.

Although hypoxia is a major stress on physiological processes, several human populations have survived for millennia at high altitudes, suggesting that they have adapted to hypoxic conditions. This hypothesis was recently corroborated by studies of Tibetan highlanders, which showed that polymorphisms in candidate genes show signatures of natural selection as well as well-replicated association signals for variation in hemoglobin levels. We extended genomic analysis to two Ethiopian ethnic groups: Amhara and Oromo. For each ethnic group, we sampled low and high altitude residents, thus allowing genetic and phenotypic comparisons across altitudes and across ethnic groups. Genome-wide SNP genotype data were collected in these samples by using Illumina arrays. We find that variants associated with hemoglobin variation among Tibetans or other variants at the same loci do not influence the trait in Ethiopians. However, in the Amhara, SNP rs10803083 is associated with hemoglobin levels at genome-wide levels of significance. No significant genotype association was observed for oxygen saturation levels in either ethnic group. Approaches based on allele frequency divergence did not detect outliers in candidate hypoxia genes, but the most differentiated variants between high- and lowlanders have a clear role in pathogen defense. Interestingly, a significant excess of allele frequency divergence was consistently detected for genes involved in cell cycle control and DNA damage and repair, thus pointing to new pathways for high altitude adaptations. Finally, a comparison of CpG methylation levels between high- and lowlanders found several significant signals at individual genes in the Oromo.
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http://dx.doi.org/10.1371/journal.pgen.1003110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3516565PMC
May 2013

Reconstructing Native American population history.

Nature 2012 Aug;488(7411):370-4

Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.

The peopling of the Americas has been the subject of extensive genetic, archaeological and linguistic research; however, central questions remain unresolved. One contentious issue is whether the settlement occurred by means of a single migration or multiple streams of migration from Siberia. The pattern of dispersals within the Americas is also poorly understood. To address these questions at a higher resolution than was previously possible, we assembled data from 52 Native American and 17 Siberian groups genotyped at 364,470 single nucleotide polymorphisms. Here we show that Native Americans descend from at least three streams of Asian gene flow. Most descend entirely from a single ancestral population that we call 'First American'. However, speakers of Eskimo-Aleut languages from the Arctic inherit almost half their ancestry from a second stream of Asian gene flow, and the Na-Dene-speaking Chipewyan from Canada inherit roughly one-tenth of their ancestry from a third stream. We show that the initial peopling followed a southward expansion facilitated by the coast, with sequential population splits and little gene flow after divergence, especially in South America. A major exception is in Chibchan speakers on both sides of the Panama isthmus, who have ancestry from both North and South America.
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http://dx.doi.org/10.1038/nature11258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3615710PMC
August 2012

Adaptations to climate-mediated selective pressures in humans.

PLoS Genet 2011 Apr 21;7(4):e1001375. Epub 2011 Apr 21.

Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America.

Humans inhabit a remarkably diverse range of environments, and adaptation through natural selection has likely played a central role in the capacity to survive and thrive in extreme climates. Unlike numerous studies that used only population genetic data to search for evidence of selection, here we scan the human genome for selection signals by identifying the SNPs with the strongest correlations between allele frequencies and climate across 61 worldwide populations. We find a striking enrichment of genic and nonsynonymous SNPs relative to non-genic SNPs among those that are strongly correlated with these climate variables. Among the most extreme signals, several overlap with those from GWAS, including SNPs associated with pigmentation and autoimmune diseases. Further, we find an enrichment of strong signals in gene sets related to UV radiation, infection and immunity, and cancer. Our results imply that adaptations to climate shaped the spatial distribution of variation in humans.
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http://dx.doi.org/10.1371/journal.pgen.1001375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3080864PMC
April 2011

Adaptations to new environments in humans: the role of subtle allele frequency shifts.

Philos Trans R Soc Lond B Biol Sci 2010 Aug;365(1552):2459-68

Department of Human Genetics, University of Chicago, 920 E. 58th Street, Chicago, IL 60637, USA.

Humans show tremendous phenotypic diversity across geographically distributed populations, and much of this diversity undoubtedly results from genetic adaptations to different environmental pressures. The availability of genome-wide genetic variation data from densely sampled populations offers unprecedented opportunities for identifying the loci responsible for these adaptations and for elucidating the genetic architecture of human adaptive traits. Several approaches have been used to detect signals of selection in human populations, and these approaches differ in the assumptions they make about the underlying mode of selection. We contrast the results of approaches based on haplotype structure and differentiation of allele frequencies to those from a method for identifying single nucleotide polymorphisms strongly correlated with environmental variables. Although the first group of approaches tends to detect new beneficial alleles that were driven to high frequencies by selection, the environmental correlation approach has power to identify alleles that experienced small shifts in frequency owing to selection. We suggest that the first group of approaches tends to identify only variants with relatively strong phenotypic effects, whereas the environmental correlation methods can detect variants that make smaller contributions to an adaptive trait.
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http://dx.doi.org/10.1098/rstb.2010.0032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2935101PMC
August 2010

Colloquium paper: human adaptations to diet, subsistence, and ecoregion are due to subtle shifts in allele frequency.

Proc Natl Acad Sci U S A 2010 May 5;107 Suppl 2:8924-30. Epub 2010 May 5.

Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.

Human populations use a variety of subsistence strategies to exploit an exceptionally broad range of ecoregions and dietary components. These aspects of human environments have changed dramatically during human evolution, giving rise to new selective pressures. To understand the genetic basis of human adaptations, we combine population genetics data with ecological information to detect variants that increased in frequency in response to new selective pressures. Our approach detects SNPs that show concordant differences in allele frequencies across populations with respect to specific aspects of the environment. Genic and especially nonsynonymous SNPs are overrepresented among those most strongly correlated with environmental variables. This provides genome-wide evidence for selection due to changes in ecoregion, diet, and subsistence. We find particularly strong signals associated with polar ecoregions, with foraging, and with a diet rich in roots and tubers. Interestingly, several of the strongest signals overlap with those implicated in energy metabolism phenotypes from genome-wide association studies, including SNPs influencing glucose levels and susceptibility to type 2 diabetes. Furthermore, several pathways, including those of starch and sucrose metabolism, are enriched for strong signals of adaptations to a diet rich in roots and tubers, whereas signals associated with polar ecoregions are overrepresented in genes associated with energy metabolism pathways.
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http://dx.doi.org/10.1073/pnas.0914625107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3024024PMC
May 2010

Genomewide linkage scan reveals novel loci modifying age of onset of Huntington's disease in the Venezuelan HD kindreds.

Genet Epidemiol 2008 Jul;32(5):445-53

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

The age of onset of Huntington's disease (HD) is inversely correlated with the CAG length in the HD gene. The CAG repeat length accounts for 70% of the variability in HD age of onset. However, 90% of individuals worldwide with expanded alleles possess between 40 and 50 CAG repeat lengths in their HD gene. For these people, the size of their repeat only determines 44% of the variability in their age of onset. Once the effect of the CAG repeat has been accounted for, the residual variance in age of onset is a heritable trait. Targeted candidate gene studies and a genome scan have suggested some loci as potential modifiers of the age of onset of HD. We analyzed the large Venezuelan kindreds in which the HD gene was originally identified. These kindreds offer greater analytic power than standard sib-pair designs. We developed novel pedigree-member selection procedures to maximize power. Using a 5,858-single-nucleotide-polymorphism marker panel, we performed a genomewide linkage analysis. We discovered two novel loci on chromosome 2. Chromosome 2p25 (logarithm of the odds ratio (LOD)=4.29) and 2q35 (LOD=3.39) may contain genes that modify age of onset. A third linkage peak on chromosome 6q22 (LOD=2.48) may confirm the most promising locus from a previous genome scan. Two other candidate loci are suggestive on chromosome 5 (LOD=3.31 at 5p14 and LOD=3.14 at 5q32). All these regions harbor candidate genes that are potential HD modifier genes. Finding these modifier genes can reveal accessible and promising new therapeutic pathways and targets to ameliorate and cure HD.
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http://dx.doi.org/10.1002/gepi.20317DOI Listing
July 2008
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