Publications by authors named "Mark Lipson"

44 Publications

Expanding the phenotype: Four new cases and hope for treatment in Bachmann-Bupp syndrome.

Am J Med Genet A 2021 11 3;185(11):3485-3493. Epub 2021 Sep 3.

Division of Medical Genetics and Genomics, Spectrum Health and Helen DeVos Children's Hospital, Grand Rapids, Michigan, USA.

Bachmann-Bupp syndrome (BABS) is a rare syndrome caused by gain-of-function variants in the C-terminus of ornithine decarboxylase (ODC coded by the ODC1 gene). BABS is characterized by developmental delay, macrocephaly, macrosomia, and an unusual pattern of non-congenital alopecia. Recent diagnosis of four more BABS patients provides further characterization of the phenotype of this syndrome including late-onset seizures in the oldest reported patient at 23 years of age, representing the first report for this phenotype in BABS. Neuroimaging abnormalities continue to be an inconsistent feature of the syndrome. This may be related to the yet unknown impact of ODC/polyamine dysregulation on the developing brain in this syndrome. Variants continue to cluster, providing support to a universal biochemical mechanism related to elevated ODC protein, enzyme activity, and abnormalities in polyamine levels. Recommendations for medical management can now be suggested as well as the potential for targeted molecular or metabolic testing when encountering this unique phenotype. The natural history of this syndrome will evolve with difluoromethylornithine (DFMO) therapy and raise new questions for further study and understanding.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.62473DOI Listing
November 2021

A genetic history of the pre-contact Caribbean.

Nature 2021 02 23;590(7844):103-110. Epub 2020 Dec 23.

Department of Genetics, Harvard Medical School, Boston, MA, USA.

Humans settled the Caribbean about 6,000 years ago, and ceramic use and intensified agriculture mark a shift from the Archaic to the Ceramic Age at around 2,500 years ago. Here we report genome-wide data from 174 ancient individuals from The Bahamas, Haiti and the Dominican Republic (collectively, Hispaniola), Puerto Rico, Curaçao and Venezuela, which we co-analysed with 89 previously published ancient individuals. Stone-tool-using Caribbean people, who first entered the Caribbean during the Archaic Age, derive from a deeply divergent population that is closest to Central and northern South American individuals; contrary to previous work, we find no support for ancestry contributed by a population related to North American individuals. Archaic-related lineages were >98% replaced by a genetically homogeneous ceramic-using population related to speakers of languages in the Arawak family from northeast South America; these people moved through the Lesser Antilles and into the Greater Antilles at least 1,700 years ago, introducing ancestry that is still present. Ancient Caribbean people avoided close kin unions despite limited mate pools that reflect small effective population sizes, which we estimate to be a minimum of 500-1,500 and a maximum of 1,530-8,150 individuals on the combined islands of Puerto Rico and Hispaniola in the dozens of generations before the individuals who we analysed lived. Census sizes are unlikely to be more than tenfold larger than effective population sizes, so previous pan-Caribbean estimates of hundreds of thousands of people are too large. Confirming a small and interconnected Ceramic Age population, we detect 19 pairs of cross-island cousins, close relatives buried around 75 km apart in Hispaniola and low genetic differentiation across islands. Genetic continuity across transitions in pottery styles reveals that cultural changes during the Ceramic Age were not driven by migration of genetically differentiated groups from the mainland, but instead reflected interactions within an interconnected Caribbean world.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-020-03053-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864882PMC
February 2021

Three Phases of Ancient Migration Shaped the Ancestry of Human Populations in Vanuatu.

Curr Biol 2020 12 15;30(24):4846-4856.e6. Epub 2020 Oct 15.

Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Department of Human Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA; Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

The archipelago of Vanuatu has been at the crossroads of human population movements in the Pacific for the past three millennia. To help address several open questions regarding the history of these movements, we generated genome-wide data for 11 ancient individuals from the island of Efate dating from its earliest settlement to the recent past, including five associated with the Chief Roi Mata's Domain World Heritage Area, and analyzed them in conjunction with 34 published ancient individuals from Vanuatu and elsewhere in Oceania, as well as present-day populations. Our results outline three distinct periods of population transformations. First, the four earliest individuals, from the Lapita-period site of Teouma, are concordant with eight previously described Lapita-associated individuals from Vanuatu and Tonga in having almost all of their ancestry from a "First Remote Oceanian" source related to East and Southeast Asians. Second, both the Papuan ancestry predominating in Vanuatu for the past 2,500 years and the smaller component of Papuan ancestry found in Polynesians can be modeled as deriving from a single source most likely originating in New Britain, suggesting that the movement of people carrying this ancestry to Remote Oceania closely followed that of the First Remote Oceanians in time and space. Third, the Chief Roi Mata's Domain individuals descend from a mixture of Vanuatu- and Polynesian-derived ancestry and are related to Polynesian-influenced communities today in central, but not southern, Vanuatu, demonstrating Polynesian genetic input in multiple groups with independent histories.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cub.2020.09.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755836PMC
December 2020

Applying f -statistics and admixture graphs: Theory and examples.

Authors:
Mark Lipson

Mol Ecol Resour 2020 Nov 19;20(6):1658-1667. Epub 2020 Aug 19.

Department of Genetics, Harvard Medical School, Boston, MA, USA.

A popular approach to learning about admixture from population genetic data is by computing the allele-sharing summary statistics known as f-statistics. Compared to some methods in population genetics, f-statistics are relatively simple, but interpreting them can still be complicated at times. In addition, f-statistics can be used to build admixture graphs (multi-population trees allowing for admixture events), which provide more explicit and thorough modelling capabilities but are correspondingly more complex to work with. Here, I discuss some of these issues to provide users of these tools with a basic guide for protocols and procedures. My focus is on the kinds of conclusions that can or cannot be drawn from the results of f -statistics and admixture graphs, illustrated with real-world examples involving human populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1755-0998.13230DOI Listing
November 2020

Ancient West African foragers in the context of African population history.

Nature 2020 01 22;577(7792):665-670. Epub 2020 Jan 22.

UCL Genetics Institute, University College London, London, UK.

Our knowledge of ancient human population structure in sub-Saharan Africa, particularly prior to the advent of food production, remains limited. Here we report genome-wide DNA data from four children-two of whom were buried approximately 8,000 years ago and two 3,000 years ago-from Shum Laka (Cameroon), one of the earliest known archaeological sites within the probable homeland of the Bantu language group. One individual carried the deeply divergent Y chromosome haplogroup A00, which today is found almost exclusively in the same region. However, the genome-wide ancestry profiles of all four individuals are most similar to those of present-day hunter-gatherers from western Central Africa, which implies that populations in western Cameroon today-as well as speakers of Bantu languages from across the continent-are not descended substantially from the population represented by these four people. We infer an Africa-wide phylogeny that features widespread admixture and three prominent radiations, including one that gave rise to at least four major lineages deep in the history of modern humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-020-1929-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8386425PMC
January 2020

Interactions between earliest Linearbandkeramik farmers and central European hunter gatherers at the dawn of European Neolithization.

Sci Rep 2019 12 20;9(1):19544. Epub 2019 Dec 20.

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

Archaeogenetic research over the last decade has demonstrated that European Neolithic farmers (ENFs) were descended primarily from Anatolian Neolithic farmers (ANFs). ENFs, including early Neolithic central European Linearbandkeramik (LBK) farming communities, also harbored ancestry from European Mesolithic hunter gatherers (WHGs) to varying extents, reflecting admixture between ENFs and WHGs. However, the timing and other details of this process are still imperfectly understood. In this report, we provide a bioarchaeological analysis of three individuals interred at the Brunn 2 site of the Brunn am Gebirge-Wolfholz archeological complex, one of the oldest LBK sites in central Europe. Two of the individuals had a mixture of WHG-related and ANF-related ancestry, one of them with approximately 50% of each, while the third individual had approximately all ANF-related ancestry. Stable carbon and nitrogen isotope ratios for all three individuals were within the range of variation reflecting diets of other Neolithic agrarian populations. Strontium isotope analysis revealed that the ~50% WHG-ANF individual was non-local to the Brunn 2 area. Overall, our data indicate interbreeding between incoming farmers, whose ancestors ultimately came from western Anatolia, and local HGs, starting within the first few generations of the arrival of the former in central Europe, as well as highlighting the integrative nature and composition of the early LBK communities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-56029-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925266PMC
December 2019

An Ancient Harappan Genome Lacks Ancestry from Steppe Pastoralists or Iranian Farmers.

Cell 2019 10 5;179(3):729-735.e10. Epub 2019 Sep 5.

Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address:

We report an ancient genome from the Indus Valley Civilization (IVC). The individual we sequenced fits as a mixture of people related to ancient Iranians (the largest component) and Southeast Asian hunter-gatherers, a unique profile that matches ancient DNA from 11 genetic outliers from sites in Iran and Turkmenistan in cultural communication with the IVC. These individuals had little if any Steppe pastoralist-derived ancestry, showing that it was not ubiquitous in northwest South Asia during the IVC as it is today. The Iranian-related ancestry in the IVC derives from a lineage leading to early Iranian farmers, herders, and hunter-gatherers before their ancestors separated, contradicting the hypothesis that the shared ancestry between early Iranians and South Asians reflects a large-scale spread of western Iranian farmers east. Instead, sampled ancient genomes from the Iranian plateau and IVC descend from different groups of hunter-gatherers who began farming without being connected by substantial movement of people.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2019.08.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800651PMC
October 2019

The formation of human populations in South and Central Asia.

Science 2019 09;365(6457)

Earth Institute, University College Dublin, Dublin 4, Ireland.

By sequencing 523 ancient humans, we show that the primary source of ancestry in modern South Asians is a prehistoric genetic gradient between people related to early hunter-gatherers of Iran and Southeast Asia. After the Indus Valley Civilization's decline, its people mixed with individuals in the southeast to form one of the two main ancestral populations of South Asia, whose direct descendants live in southern India. Simultaneously, they mixed with descendants of Steppe pastoralists who, starting around 4000 years ago, spread via Central Asia to form the other main ancestral population. The Steppe ancestry in South Asia has the same profile as that in Bronze Age Eastern Europe, tracking a movement of people that affected both regions and that likely spread the distinctive features shared between Indo-Iranian and Balto-Slavic languages.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.aat7487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822619PMC
September 2019

Ancient DNA reveals a multistep spread of the first herders into sub-Saharan Africa.

Science 2019 07 30;365(6448). Epub 2019 May 30.

Department of Anthropology, California State University, San Bernardino, CA 92407, USA.

How food production first entered eastern Africa ~5000 years ago and the extent to which people moved with livestock is unclear. We present genome-wide data from 41 individuals associated with Later Stone Age, Pastoral Neolithic (PN), and Iron Age contexts in what are now Kenya and Tanzania to examine the genetic impacts of the spreads of herding and farming. Our results support a multiphase model in which admixture between northeastern African-related peoples and eastern African foragers formed multiple pastoralist groups, including a genetically homogeneous PN cluster. Additional admixture with northeastern and western African-related groups occurred by the Iron Age. These findings support several movements of food producers while rejecting models of minimal admixture with foragers and of genetic differentiation between makers of distinct PN artifacts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.aaw6275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6827346PMC
July 2019

Mutation update for the SATB2 gene.

Hum Mutat 2019 08 18;40(8):1013-1029. Epub 2019 Jun 18.

Department of Genetics, Cook Chldren's Medical Center, Fort Worth, Texas.

SATB2-associated syndrome (SAS) is an autosomal dominant neurodevelopmental disorder caused by alterations in the SATB2 gene. Here we present a review of published pathogenic variants in the SATB2 gene to date and report 38 novel alterations found in 57 additional previously unreported individuals. Overall, we present a compilation of 120 unique variants identified in 155 unrelated families ranging from single nucleotide coding variants to genomic rearrangements distributed throughout the entire coding region of SATB2. Single nucleotide variants predicted to result in the occurrence of a premature stop codon were the most commonly seen (51/120 = 42.5%) followed by missense variants (31/120 = 25.8%). We review the rather limited functional characterization of pathogenic variants and discuss current understanding of the consequences of the different molecular alterations. We present an expansive phenotypic review along with novel genotype-phenotype correlations. Lastly, we discuss current knowledge of animal models and present future prospects. This review should help provide better guidance for the care of individuals diagnosed with SAS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.23771DOI Listing
August 2019

Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway.

Am J Hum Genet 2019 02 10;104(2):213-228. Epub 2019 Jan 10.

Service de Génétique Médicale, CHU de Nantes, 44000 Nantes, France; Inserm, CNRS, Univ Nantes, l'institut du thorax, 44000 Nantes, France.

Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61%) individuals. In addition to TBX4, the overlapping ∼2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2018.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369446PMC
February 2019

Practice and attitudes regarding double gloving among staff surgeons and surgical trainees.

Can J Surg 2018 08;61(4):244-250

From the Department of Surgery, University of Calgary, Calgary, Alta. (Lipson, Ball, Grondin); the Department of Production Animal Health, Faculty of Veterinary Medicine and Department of Mathematics and Statistics, Faculty of Science, University of Calgary, Calgary, Alta. (Deardon); and the Department of Surgery, University of Alberta, Edmonton, Alta. (Switzer, de Gara).

Background: Despite supporting evidence, many staff surgeons and surgical trainees do not routinely double glove. We performed a study to assess rates of and attitudes toward double gloving and the use of eye protection in the operating room.

Methods: We conducted an electronic survey among all staff surgeons and surgical trainees at 2 tertiary care centres in Alberta between September and November 2015.We analyzed the data using log-binomial regression for binary outcomes to account for multiple independent variables and interactions. For 2-group comparisons, we used a 2-group test of proportions.

Results: The response rate was 34.3% (361/1051); 205/698 staff surgeons (29.4%) and 156/353 surgical trainees (44.2%) responded. Trainees were more likely than staff surgeons to ever double glove in the operating room ( = 0.01) and to do so routinely ( = 0.01). Staff surgeons were more likely than trainees to never double glove ( = 0.01). A total of 300/353 respondents (85.0%) reported using eye protection routinely in the operating room. Needle-stick injury was common (184 staff surgeons [92.5%], 115 trainees [74.7%]). Reduced tactile feedback, decreased manual dexterity and discomfort/poor fit were perceived barriers to double gloving.

Conclusion: Rates of double gloving leave room for improvement. Surgical trainees were more likely than staff surgeons to double glove. Barriers remain to routine double gloving among staff surgeons and trainees. Increased education on the benefits of double gloving and early introduction of this practice may increase uptake.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066380PMC
August 2018

Practice and attitudes regarding double gloving among staff surgeons and surgical trainees.

Can J Surg 2018 Jun 1;61(4):13616. Epub 2018 Jun 1.

From the Department of Surgery, University of Calgary, Calgary, Alta. (Lipson, Ball, Grondin); the Department of Production Animal Health, Faculty of Veterinary Medicine and Department of Mathematics and Statistics, Faculty of Science, University of Calgary, Calgary, Alta. (Deardon); and the Department of Surgery, University of Alberta, Edmonton, Alta. (Switzer, de Gara).

Background: Despite supporting evidence, many staff surgeons and surgical trainees do not routinely double glove. We performed a study to assess rates of and attitudes toward double gloving and the use of eye protection in the operating room.

Methods: We conducted an electronic survey among all staff surgeons and surgical trainees at 2 tertiary care centres in Alberta between September and November 2015.We analyzed the data using log-binomial regression for binary outcomes to account for multiple independent variables and interactions. For 2-group comparisons, we used a 2-group test of proportions.

Results: The response rate was 34.3% (361/1051); 205/698 staff surgeons (29.4%) and 156/353 surgical trainees (44.2%) responded. Trainees were more likely than staff surgeons to ever double glove in the operating room ( = 0.01) and to do so routinely ( = 0.01). Staff surgeons were more likely than trainees to never double glove ( = 0.01). A total of 300/353 respondents (85.0%) reported using eye protection routinely in the operating room. Needle-stick injury was common (184 staff surgeons [92.5%], 115 trainees [74.7%]). Reduced tactile feedback, decreased manual dexterity and discomfort/poor fit were perceived barriers to double gloving.

Conclusion: Rates of double gloving leave room for improvement. Surgical trainees were more likely than staff surgeons to double glove. Barriers remain to routine double gloving among staff surgeons and trainees. Increased education on the benefits of double gloving and early introduction of this practice may increase uptake.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1503/cjs.013616DOI Listing
June 2018

Ancient genomes document multiple waves of migration in Southeast Asian prehistory.

Science 2018 07 17;361(6397):92-95. Epub 2018 May 17.

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

Southeast Asia is home to rich human genetic and linguistic diversity, but the details of past population movements in the region are not well known. Here, we report genome-wide ancient DNA data from 18 Southeast Asian individuals spanning from the Neolithic period through the Iron Age (4100 to 1700 years ago). Early farmers from Man Bac in Vietnam exhibit a mixture of East Asian (southern Chinese agriculturalist) and deeply diverged eastern Eurasian (hunter-gatherer) ancestry characteristic of Austroasiatic speakers, with similar ancestry as far south as Indonesia providing evidence for an expansive initial spread of Austroasiatic languages. By the Bronze Age, in a parallel pattern to Europe, sites in Vietnam and Myanmar show close connections to present-day majority groups, reflecting substantial additional influxes of migrants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.aat3188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6476732PMC
July 2018

Population Turnover in Remote Oceania Shortly after Initial Settlement.

Curr Biol 2018 04 28;28(7):1157-1165.e7. Epub 2018 Feb 28.

Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston, MA 02115, USA; Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Max Planck-Harvard Research Center for the Archaeoscience of the Ancient Mediterranean, Cambridge, MA 02138, USA. Electronic address:

Ancient DNA from Vanuatu and Tonga dating to about 2,900-2,600 years ago (before present, BP) has revealed that the "First Remote Oceanians" associated with the Lapita archaeological culture were directly descended from the population that, beginning around 5000 BP, spread Austronesian languages from Taiwan to the Philippines, western Melanesia, and eventually Remote Oceania. Thus, ancestors of the First Remote Oceanians must have passed by the Papuan-ancestry populations they encountered in New Guinea, the Bismarck Archipelago, and the Solomon Islands with minimal admixture [1]. However, all present-day populations in Near and Remote Oceania harbor >25% Papuan ancestry, implying that additional eastward migration must have occurred. We generated genome-wide data for 14 ancient individuals from Efate and Epi Islands in Vanuatu from 2900-150 BP, as well as 185 present-day individuals from 18 islands. We find that people of almost entirely Papuan ancestry arrived in Vanuatu by around 2300 BP, most likely reflecting migrations a few hundred years earlier at the end of the Lapita period, when there is also evidence of changes in skeletal morphology and cessation of long-distance trade between Near and Remote Oceania [2, 3]. Papuan ancestry was subsequently diluted through admixture but remains at least 80%-90% in most islands. Through a fine-grained analysis of ancestry profiles, we show that the Papuan ancestry in Vanuatu derives from the Bismarck Archipelago rather than the geographically closer Solomon Islands. However, the Papuan ancestry in Polynesia-the most remote Pacific islands-derives from different sources, documenting a third stream of migration from Near to Remote Oceania.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cub.2018.02.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882562PMC
April 2018

A comprehensive genomic history of extinct and living elephants.

Proc Natl Acad Sci U S A 2018 03 26;115(11):E2566-E2574. Epub 2018 Feb 26.

Broad Institute of MIT and Harvard, Cambridge, MA 02142.

Elephantids are the world's most iconic megafaunal family, yet there is no comprehensive genomic assessment of their relationships. We report a total of 14 genomes, including 2 from the American mastodon, which is an extinct elephantid relative, and 12 spanning all three extant and three extinct elephantid species including an ∼120,000-y-old straight-tusked elephant, a Columbian mammoth, and woolly mammoths. Earlier genetic studies modeled elephantid evolution via simple bifurcating trees, but here we show that interspecies hybridization has been a recurrent feature of elephantid evolution. We found that the genetic makeup of the straight-tusked elephant, previously placed as a sister group to African forest elephants based on lower coverage data, in fact comprises three major components. Most of the straight-tusked elephant's ancestry derives from a lineage related to the ancestor of African elephants while its remaining ancestry consists of a large contribution from a lineage related to forest elephants and another related to mammoths. Columbian and woolly mammoths also showed evidence of interbreeding, likely following a latitudinal cline across North America. While hybridization events have shaped elephantid history in profound ways, isolation also appears to have played an important role. Our data reveal nearly complete isolation between the ancestors of the African forest and savanna elephants for ∼500,000 y, providing compelling justification for the conservation of forest and savanna elephants as separate species.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1720554115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5856550PMC
March 2018

The Beaker phenomenon and the genomic transformation of northwest Europe.

Nature 2018 03 21;555(7695):190-196. Epub 2018 Feb 21.

Departamento de Prehistoria y Arqueología, Universidad Autónoma de Madrid, Madrid 28049, Spain.

From around 2750 to 2500 bc, Bell Beaker pottery became widespread across western and central Europe, before it disappeared between 2200 and 1800 bc. The forces that propelled its expansion are a matter of long-standing debate, and there is support for both cultural diffusion and migration having a role in this process. Here we present genome-wide data from 400 Neolithic, Copper Age and Bronze Age Europeans, including 226 individuals associated with Beaker-complex artefacts. We detected limited genetic affinity between Beaker-complex-associated individuals from Iberia and central Europe, and thus exclude migration as an important mechanism of spread between these two regions. However, migration had a key role in the further dissemination of the Beaker complex. We document this phenomenon most clearly in Britain, where the spread of the Beaker complex introduced high levels of steppe-related ancestry and was associated with the replacement of approximately 90% of Britain's gene pool within a few hundred years, continuing the east-to-west expansion that had brought steppe-related ancestry into central and northern Europe over the previous centuries.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature25738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5973796PMC
March 2018

Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy.

J Clin Invest 2018 04 12;128(4):1496-1508. Epub 2018 Mar 12.

Plastic Surgery, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.

Background: Sporadic vascular malformations (VMs) are complex congenital anomalies of blood vessels that lead to stroke, life-threatening bleeds, disfigurement, overgrowth, and/or pain. Therapeutic options are severely limited, and multidisciplinary management remains challenging, particularly for high-flow arteriovenous malformations (AVM).

Methods: To investigate the pathogenesis of sporadic intracranial and extracranial VMs in 160 children in which known genetic causes had been excluded, we sequenced DNA from affected tissue and optimized analysis for detection of low mutant allele frequency.

Results: We discovered multiple mosaic-activating variants in 4 genes of the RAS/MAPK pathway, KRAS, NRAS, BRAF, and MAP2K1, a pathway commonly activated in cancer and responsible for the germline RAS-opathies. These variants were more frequent in high-flow than low-flow VMs. In vitro characterization and 2 transgenic zebrafish AVM models that recapitulated the human phenotype validated the pathogenesis of the mutant alleles. Importantly, treatment of AVM-BRAF mutant zebrafish with the BRAF inhibitor vemurafinib restored blood flow in AVM.

Conclusion: Our findings uncover a major cause of sporadic VMs of different clinical types and thereby offer the potential of personalized medical treatment by repurposing existing licensed cancer therapies.

Funding: This work was funded or supported by grants from the AVM Butterfly Charity, the Wellcome Trust (UK), the Medical Research Council (UK), the UK National Institute for Health Research, the L'Oreal-Melanoma Research Alliance, the European Research Council, and the National Human Genome Research Institute (US).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI98589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5873857PMC
April 2018

Parallel palaeogenomic transects reveal complex genetic history of early European farmers.

Nature 2017 11 8;551(7680):368-372. Epub 2017 Nov 8.

Laczkó Dezso˝ Museum, Veszprém 8200, Hungary.

Ancient DNA studies have established that Neolithic European populations were descended from Anatolian migrants who received a limited amount of admixture from resident hunter-gatherers. Many open questions remain, however, about the spatial and temporal dynamics of population interactions and admixture during the Neolithic period. Here we investigate the population dynamics of Neolithization across Europe using a high-resolution genome-wide ancient DNA dataset with a total of 180 samples, of which 130 are newly reported here, from the Neolithic and Chalcolithic periods of Hungary (6000-2900 bc, n = 100), Germany (5500-3000 bc, n = 42) and Spain (5500-2200 bc, n = 38). We find that genetic diversity was shaped predominantly by local processes, with varied sources and proportions of hunter-gatherer ancestry among the three regions and through time. Admixture between groups with different ancestry profiles was pervasive and resulted in observable population transformation across almost all cultural transitions. Our results shed new light on the ways in which gene flow reshaped European populations throughout the Neolithic period and demonstrate the potential of time-series-based sampling and modelling approaches to elucidate multiple dimensions of historical population interactions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature24476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5973800PMC
November 2017

A Working Model of the Deep Relationships of Diverse Modern Human Genetic Lineages Outside of Africa.

Mol Biol Evol 2017 04;34(4):889-902

Department of Genetics, Harvard Medical School, Boston, MA.

A major topic of interest in human prehistory is how the large-scale genetic structure of modern populations outside of Africa was established. Demographic models have been developed that capture the relationships among small numbers of populations or within particular geographical regions, but constructing a phylogenetic tree with gene flow events for a wide diversity of non-Africans remains a difficult problem. Here, we report a model that provides a good statistical fit to allele-frequency correlation patterns among East Asians, Australasians, Native Americans, and ancient western and northern Eurasians, together with archaic human groups. The model features a primary eastern/western bifurcation dating to at least 45,000 years ago, with Australasians nested inside the eastern clade, and a parsimonious set of admixture events. While our results still represent a simplified picture, they provide a useful summary of deep Eurasian population history that can serve as a null model for future studies and a baseline for further discoveries.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/molbev/msw293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5400393PMC
April 2017

Genomic insights into the peopling of the Southwest Pacific.

Nature 2016 Oct 3;538(7626):510-513. Epub 2016 Oct 3.

School of Archaeology and Earth Institute, Belfield, University College Dublin, Dublin 4, Dublin, Ireland.

The appearance of people associated with the Lapita culture in the South Pacific around 3,000 years ago marked the beginning of the last major human dispersal to unpopulated lands. However, the relationship of these pioneers to the long-established Papuan people of the New Guinea region is unclear. Here we present genome-wide ancient DNA data from three individuals from Vanuatu (about 3,100-2,700 years before present) and one from Tonga (about 2,700-2,300 years before present), and analyse them with data from 778 present-day East Asians and Oceanians. Today, indigenous people of the South Pacific harbour a mixture of ancestry from Papuans and a population of East Asian origin that no longer exists in unmixed form, but is a match to the ancient individuals. Most analyses have interpreted the minimum of twenty-five per cent Papuan ancestry in the region today as evidence that the first humans to reach Remote Oceania, including Polynesia, were derived from population mixtures near New Guinea, before their further expansion into Remote Oceania. However, our finding that the ancient individuals had little to no Papuan ancestry implies that later human population movements spread Papuan ancestry through the South Pacific after the first peopling of the islands.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature19844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5515717PMC
October 2016

Postoperative Nonsteroidal Anti-inflammatory Drug Use and Intestinal Anastomotic Dehiscence: A Systematic Review and Meta-Analysis.

Dis Colon Rectum 2016 Nov;59(11):1087-1097

Department of Surgery, University of Calgary and the Foothills Medical Centre, Calgary, Alberta, Canada.

Background: Nonsteroidal anti-inflammatory drugs are commonly used analgesics in colorectal surgery. Controversy exists regarding the potential association between these drugs and anastomotic dehiscence.

Objective: This study aimed to determine whether postoperative nonsteroidal anti-inflammatory drug use is associated with intestinal anastomotic dehiscence.

Data Sources: PubMed, EMBASE, CENTRAL, and references of included articles were searched without date or language restriction.

Study Selection: Randomized controlled trials and observational studies that compared postoperative nonsteroidal anti-inflammatory drug use with nonuse and reported on intestinal anastomotic dehiscence were selected.

Intervention: The use of postoperative nonsteroidal anti-inflammatory drugs relative to placebo or nonuse was investigated.

Main Outcome Measures: Risk ratios and adjusted or unadjusted odds ratios for anastomotic dehiscence were pooled across randomized controlled trials and observational studies using DerSimonian and Laird random-effects models.

Results: Among 4395 citations identified, 6 randomized controlled trials (n = 473 patients) and 11 observational studies (n > 20,184 patients) were included. Pooled analyses revealed that nonsteroidal anti-inflammatory drug use was nonsignificantly associated with anastomotic dehiscence in randomized controlled trials (risk ratio, 1.96; 95% CI, 0.74-5.16; I = 0%) and significantly associated with anastomotic dehiscence in observational studies (OR, 1.46; 95% CI, 1.14-1.86; I = 54%). In stratified analyses of observational study data, the pooled OR for anastomotic dehiscence was statistically significant for studies of nonselective nonsteroidal anti-inflammatory drug use (6 studies; > 4900 patients; OR, 2.09; 95% CI, 1.65-2.64; I = 0%), but was not statistically significant for studies of cyclooxygenase-2 selective nonsteroidal anti-inflammatory drug use (3 studies; >697 patients; OR, 1.34; 95% CI, 0.78-2.31; I = 0%).

Limitations: Studies varied by patient selection criteria, drug exposures, and definitions of anastomotic dehiscence. Analyses of randomized controlled trials and cyclooxygenase-2 selective nonsteroidal anti-inflammatory drugs were potentially underpowered.

Conclusions: Pooled observational data suggest an association between postoperative nonsteroidal anti-inflammatory drug use and intestinal anastomotic dehiscence. Caution may be warranted in using these medications in patients at risk for this complication.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/DCR.0000000000000666DOI Listing
November 2016

The Simons Genome Diversity Project: 300 genomes from 142 diverse populations.

Nature 2016 Oct 21;538(7624):201-206. Epub 2016 Sep 21.

Department of Zoology, University of Oxford, Oxford OX1 3PS, UK.

Here we report the Simons Genome Diversity Project data set: high quality genomes from 300 individuals from 142 diverse populations. These genomes include at least 5.8 million base pairs that are not present in the human reference genome. Our analysis reveals key features of the landscape of human genome variation, including that the rate of accumulation of mutations has accelerated by about 5% in non-Africans compared to Africans since divergence. We show that the ancestors of some pairs of present-day human populations were substantially separated by 100,000 years ago, well before the archaeologically attested onset of behavioural modernity. We also demonstrate that indigenous Australians, New Guineans and Andamanese do not derive substantial ancestry from an early dispersal of modern humans; instead, their modern human ancestry is consistent with coming from the same source as that of other non-Africans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature18964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161557PMC
October 2016

The genetic history of Ice Age Europe.

Nature 2016 06 2;534(7606):200-5. Epub 2016 May 2.

Instituto Internacional de Investigaciones Prehistóricas, Universidad de Cantabria, 39005 Santander, Spain.

Modern humans arrived in Europe ~45,000 years ago, but little is known about their genetic composition before the start of farming ~8,500 years ago. Here we analyse genome-wide data from 51 Eurasians from ~45,000-7,000 years ago. Over this time, the proportion of Neanderthal DNA decreased from 3-6% to around 2%, consistent with natural selection against Neanderthal variants in modern humans. Whereas there is no evidence of the earliest modern humans in Europe contributing to the genetic composition of present-day Europeans, all individuals between ~37,000 and ~14,000 years ago descended from a single founder population which forms part of the ancestry of present-day Europeans. An ~35,000-year-old individual from northwest Europe represents an early branch of this founder population which was then displaced across a broad region, before reappearing in southwest Europe at the height of the last Ice Age ~19,000 years ago. During the major warming period after ~14,000 years ago, a genetic component related to present-day Near Easterners became widespread in Europe. These results document how population turnover and migration have been recurring themes of European prehistory.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature17993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4943878PMC
June 2016

Calibrating the Human Mutation Rate via Ancestral Recombination Density in Diploid Genomes.

PLoS Genet 2015 Nov 12;11(11):e1005550. Epub 2015 Nov 12.

Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.

The human mutation rate is an essential parameter for studying the evolution of our species, interpreting present-day genetic variation, and understanding the incidence of genetic disease. Nevertheless, our current estimates of the rate are uncertain. Most notably, recent approaches based on counting de novo mutations in family pedigrees have yielded significantly smaller values than classical methods based on sequence divergence. Here, we propose a new method that uses the fine-scale human recombination map to calibrate the rate of accumulation of mutations. By comparing local heterozygosity levels in diploid genomes to the genetic distance scale over which these levels change, we are able to estimate a long-term mutation rate averaged over hundreds or thousands of generations. We infer a rate of 1.61 ± 0.13 × 10-8 mutations per base per generation, which falls in between phylogenetic and pedigree-based estimates, and we suggest possible mechanisms to reconcile our estimate with previous studies. Our results support intermediate-age divergences among human populations and between humans and other great apes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.1005550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4642934PMC
November 2015

No evidence of locus heterogeneity in familial microcephaly with or without chorioretinopathy, lymphedema, or mental retardation syndrome.

Orphanet J Rare Dis 2015 May 2;10:52. Epub 2015 May 2.

Laboratory of Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Avenue Hippocrate 74, bte B1.74.06, B-1200, Brussels, Belgium.

Background: Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation syndrome (MCLMR) is a rare autosomal dominant disorder with variable expressivity. It is characterized by mild-to-severe microcephaly, often associated with intellectual disability, ocular defects and lymphedema. It can be sporadic or inherited. Eighty-seven patients have been described to carry a mutation in KIF11, which encodes a homotetrameric motor kinesin, EG5.

Methods: We tested 23 unreported MCLMR index patients for KIF11. We also reviewed the clinical phenotypes of all our patients as well as of those described in previously published studies.

Results: We identified 14 mutations, 12 of which are novel. We detected mutations in 12 affected individuals, from 6 out of 6 familial cases, and in 8 out of 17 sporadic patients. Phenotypic evaluation of patients (our 26 + 61 earlier published = 87) revealed microcephaly in 91%, eye anomalies in 72%, intellectual disability in 67% and lymphedema in 47% of the patients. Unaffected carriers were rare (4 out of 87: 5%). Family history is not a requisite for diagnosis; 31% (16 out of 52) were de novo cases.

Conclusions: All inherited cases, and 50% of sporadic cases of MCLMR are due to germline KIF11 mutations. It is possible that mosaic KIF11 mutations cause the remainder of sporadic cases, which the methods employed here were not designed to detect. On the other hand, some of them might have another mimicking disorder and genetic defect, as microcephaly is highly heterogeneous. In aggregate, KIF11 mutations likely cause the majority, if not all, of MCLMR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13023-015-0271-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4464120PMC
May 2015

Ancient human genomes suggest three ancestral populations for present-day Europeans.

Nature 2014 Sep;513(7518):409-13

Center for Global Health and Child Development, Kisumu 40100, Kenya.

We sequenced the genomes of a ∼7,000-year-old farmer from Germany and eight ∼8,000-year-old hunter-gatherers from Luxembourg and Sweden. We analysed these and other ancient genomes with 2,345 contemporary humans to show that most present-day Europeans derive from at least three highly differentiated populations: west European hunter-gatherers, who contributed ancestry to all Europeans but not to Near Easterners; ancient north Eurasians related to Upper Palaeolithic Siberians, who contributed to both Europeans and Near Easterners; and early European farmers, who were mainly of Near Eastern origin but also harboured west European hunter-gatherer related ancestry. We model these populations' deep relationships and show that early European farmers had ∼44% ancestry from a 'basal Eurasian' population that split before the diversification of other non-African lineages.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature13673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4170574PMC
September 2014
-->