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It is now widely accepted that agriculture and settled village life arrived in Europe as a cultural package, carried by people migrating from Anatolia and the Aegean Basin. The putative fisher-forager site of Lepenski Vir in Serbia has long been acknowledged as an exception to this model. Here, the Mesolithic–Neolithic transition—possibly inspired by interaction with the new arrivals—was thought to have taken place autochthonously on site. Our reinterpretation, based on ancient genomes, as well as archaeological and isotopic evidence, indicates that here, too, house construction, early village society and agriculture were primarily associated with Europe’s first farmers, thus challenging the long-held view of Lepenski Vir as a Mesolithic community that adopted Neolithic practices. Although aspects of the site's occupation, such as the trapezoidal houses, were inspired by local Mesolithic traditions, it is far from certain that the village was founded by Iron Gates foragers. A detailed timeline of population changes at the site suggests that Aegean incomers did not simply integrate into an established Mesolithic society, but rather founded new lineages and households. Iron Gates foragers and their admixed descendants largely appear to have been buried separately, on the fringes of the settlement. The diet of those buried outside in pits shows no major shift from aquatic to terrestrial food resources.

The precise genetic origins of the first Neolithic farming populations in Europe and Southwest Asia, as well as the processes and the timing of their differentiation, remain largely unknown. Demogenomic modeling of high-quality ancient genomes reveals that the early farmers of Anatolia and Europe emerged from a multiphase mixing of a Southwest Asian population with a strongly bottlenecked western hunter-gatherer population after the last glacial maximum. Moreover, the ancestors of the first farmers of Europe and Anatolia went through a period of extreme genetic drift during their westward range expansion, contributing highly to their genetic distinctiveness. This modeling elucidates the demographic processes at the root of the Neolithic transition and leads to a spatial interpretation of the population history of Southwest Asia and Europe during the late Pleistocene and early Holocene., Cell, 185 (11), ISSN:0092-8674, ISSN:1097-4172

Genomic regions under positive selection harbour variation linked for example to adaptation. Most tools for detecting positively selected variants have computational resource requirements rendering them impractical on population genomic datasets with hundreds of thousands of individuals or more. We have developed and implemented an efficient haplotype-based approach able to scan large datasets and accurately detect positive selection. We achieve this by combining a pattern matching approach based on the positional Burrows-Wheeler transform with model-based inference which only requires the evaluation of closed-form expressions. We evaluate our approach with simulations, and find it to be both sensitive and specific. The computational resource requirements quantified using UK Biobank data indicate that our implementation is scalable to population genomic datasets with millions of individuals. Our approach may serve as an algorithmic blueprint for the era of 'big data' genomics: a combinatorial core coupled with statistical inference in closed form. © The Author(s) 2023. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.

Today, it is widely accepted that agriculture and settled village life arrived in Europe as a cultural package, carried by people migrating from Anatolia and the Aegean Basin. The putative fisher-forager site of Lepenski Vir in Serbia has long been acknowledged as an exception to this model. Here, the Mesolithic-Neolithic transition - possibly inspired by interaction with the new arrivals - was thought to have taken place autochthonously on site. Our reinterpretation, based on ancient genomes, as well as archaeological and isotopic evidence, revisits this conclusion, indicating that here too, house construction, early village society and agriculture were primarily associated with Europe’s first farmers, thus challenging the long-held interpretation of Lepenski Vir as a Mesolithic community that adopted Neolithic practices. A detailed timeline of population changes at the site suggests that Aegean incomers did not simply integrate into an established Mesolithic society, rather founded new lineages and households. Iron Gates foragers and their admixed descendants appear to have been buried largely separately, on the fringes of the settlement, their diet showing no major shift from aquatic to terrestrial food resources.

We report genome sequence data from six individuals excavated from the base of a medieval well at a site in Norwich, UK. A revised radiocarbon analysis of the assemblage is consistent with these individuals being part of a historically attested episode of antisemitic violence on 6 February 1190 CE. We find that four of these individuals were closely related and all six have strong genetic affinities with modern Ashkenazi Jews. We identify four alleles associated with genetic disease in Ashkenazi Jewish populations and infer variation in pigmentation traits, including the presence of red hair. Simulations indicate that Ashkenazi-associated genetic disease alleles were already at appreciable frequencies, centuries earlier than previously hypothesized. These findings provide new insights into a significant historical crime, into Ashkenazi population history, and into the origins of genetic diseases associated with modern Jewish populations.

This contribution describes the discovery and subsequent investigation of a cist in a rock-cut pit at Achavanich, Highland. Discovered and excavated in 1987, the cist was found to contain the tightly contracted skeletal remains of a young woman, accompanied by a Beaker, three flint artefacts and a cattle scapula. Initial post excavation work established a date for the skeleton together with details of her age and sex, and preliminary pollen analysis of sediments attaching to the Beaker was undertaken. The findings were never fully published and, upon the death of the excavator, Robert Gourlay, the documentary archive was left in the Highland Council Archaeology Unit. Fresh research in 2014–17, initiated and co-ordinated by the first-named author and funded by the Society of Antiquaries of Scotland with assistance from National Museums Scotland, the Natural History Museum and Harvard Medical School, has produced a significant amount of new information on the individual and on some of the items with which she was buried. This new information includes two further radiocarbon dates, a more detailed osteological report, isotopic information pertaining to the place where she had been raised and to her diet, histological information on the decomposition of her body, and genetic information that sheds light on her ancestry, her hair, eye and skin colour and her intolerance of lactose. (This is the first time that an ancient DNA report has been published in the Proceedings.) Moreover, a facial reconstruction adds virtual flesh to her bones. The significance of this discovery within the Chalcolithic to Early Bronze Age of this part of Scotland is discussed, along with the many and innovative ways in which information on this individual, dubbed ‘Ava’, has been disseminated around the world.

In European and many African, Middle Eastern and southern Asian populations, lactase persistence (LP) is the most strongly selected monogenic trait to have evolved over the past 10,000 years1. Although the selection of LP and the consumption of prehistoric milk must be linked, considerable uncertainty remains concerning their spatiotemporal configuration and specific interactions2,3. Here we provide detailed distributions of milk exploitation across Europe over the past 9,000 years using around 7,000 pottery fat residues from more than 550 archaeological sites. European milk use was widespread from the Neolithic period onwards but varied spatially and temporally in intensity. Notably, LP selection varying with levels of prehistoric milk exploitation is no better at explaining LP allele frequency trajectories than uniform selection since the Neolithic period. In the UK Biobank4,5 cohort of 500,000 contemporary Europeans, LP genotype was only weakly associated with milk consumption and did not show consistent associations with improved fitness or health indicators. This suggests that other reasons for the beneficial effects of LP should be considered for its rapid frequency increase. We propose that lactase non-persistent individuals consumed milk when it became available but, under conditions of famine and/or increased pathogen exposure, this was disadvantageous, driving LP selection in prehistoric Europe. Comparison of model likelihoods indicates that population fluctuations, settlement density and wild animal exploitation—proxies for these drivers—provide better explanations of LP selection than the extent of milk exploitation. These findings offer new perspectives on prehistoric milk exploitation and LP evolution.

The precise genetic origins of the first Neolithic farming populations, as well as the processes and the timing of their differentiation, remain largely unknown. Based on demogenomic modeling of high-quality ancient genomes, we show that the early farmers of Anatolia and Europe emerged from a multiphase mixing of a Near Eastern population with a strongly bottlenecked Western hunter-gatherer population after the Last Glacial Maximum. Moreover, the population branch leading to the first farmers of Europe and Anatolia is characterized by a 2,500-year period of extreme genetic drift during its westward range expansion. Based on these findings, we derive a spatially explicit model of the population history of Southwest Asia and Europe during the late Pleistocene and early Holocene.One-Sentence Summary:Early European farmers emerged from multiple post LGM mixtures and experienced extreme drift during their westward expansion.

Lactase persistence (LP), the continued expression of lactase into adulthood, is the most strongly selected single gene trait over the last 10,000 years inmultiple human populations. It has been posited that the primary allele causing LP among Eurasians, rs4988235-A [1], only rose to appreciable frequencies during the Bronze and Iron Ages [2, 3], long after humans started consuming milk from domesticated animals. This rapid rise has been attributed to an influx of people from the Pontic-Caspian steppe that began around 5,000 years ago [4, 5]. We investigate the spatiotemporal spread of LP through an analysis of 14 warriors from the Tollense Bronze Age battlefield in northern Germany ( 3,200 before present, BP), the oldest large-scale conflict site north of the Alps. Genetic data indicate that these individuals represent a single unstructured Central/Northern European population.We complemented these data with genotypes of 18 individuals fromtheBronzeAge siteMokrin in Serbia ( 4,100 to 3,700 BP) and 37 individuals from Eastern Europe and the Pontic-Caspian Steppe region, predating both Bronze Age sites ( 5,980 to 3,980BP).We infer lowLPin all three regions, i.e., in northern Germany and South-eastern and Eastern Europe, suggesting that the surge of rs4988235 in Central and NorthernEuropewas unlikely caused by Steppe expansions.We estimate a selection coefficientof 0.06 and conclude that the selection was ongoing in various parts of Europe over the last 3,000 years.

Twenty-four ancient genomes with an average sequencing coverage of 0.85±0.25 X were produced from the Mokrin necropolis, an Early Bronze Age (2,100-1,800 BC) Maros culture site in Serbia, to provide unambiguous identification of biological sex, population structure, and genetic kinship between individuals. Of the 24 investigated individuals, 15 were involved in kinship relationships of varying degrees, including 3 parent-offspring relationships. All observed parent-offspring pairs were mother and son. In addition to the absence of biological daughters, we observed a number of young women and girls with no biological relatives in our sample. These observations, together with the high mitochondrial diversity in our sample, are consistent with the practice of female exogamy in the population served by Mokrin. However, moderate-to-high Y-chromosomal diversity suggests a degree of male mobility greater than that expected under strict patrilocality. Individual status differences at Mokrin, as indicated by grave goods, support the inference that females could inherit status, but could not transmit status to all their sons. The case of a son whose grave good richness outstrips that of his biological mother suggests that sons had the possibility to acquire status during their lifetimes. The Mokrin sample resembles a genetically unstructured population, suggesting that the community’s social hierarchies were not accompanied by strict marriage barriers.

Lactase persistence (LP), the continued expression of lactase into adulthood, is the most strongly selected single gene trait over the last 10,000 years in multiple human populations. It has been posited that the primary allele causing LP among Eurasians, rs4988235*T (Enattah et al. 2008), only rose to appreciable frequencies during the Bronze and Iron Ages (Mathieson et al 2015; Olalde et al. 2018), long after humans started consuming milk from domesticated animals. This rapid rise has been attributed to an influx of peoples from the Pontic-Caspian steppe that began around 5,000 years ago (Allentoft et al. 2015; Furholt et al. 2016). We investigate the spatiotemporal spread of LP through an analysis of 14 warriors from the Tollense Bronze Age battlefield in northern Germany (~3,200 BP); the oldest large-scale conflict site north of the Alps. Genetic data indicate that these individuals represent a single unstructured Central/Northern European population. We complemented these data with genotypes of 18 individuals from the Bronze Age site Mokrin in Serbia (~4,100 to ~3,700 BP) and 37 individuals from eastern Europe and the Pontic-Caspian Steppe region, predating both Bronze Age sites (~5,980 to ~4,250 BP). We infer low LP in all three regions, i.e. in northern Germany, south- eastern, and eastern Europe, suggesting that the surge of rs4988235 in Central and Northern Europe was unlikely caused by Steppe expansions. We estimate a selection coefficient of 0.06, and conclude that the selection was on-going in various parts of Europe over the last 3,000 years.

The XAF1-E134* variant increases the cancer risk for carriers of the TP53-R337H allele., Cancer risk is highly variable in carriers of the common TP53-R337H founder allele, possibly due to the influence of modifier genes. Whole-genome sequencing identified a variant in the tumor suppressor XAF1 (E134*/Glu134Ter/rs146752602) in a subset of R337H carriers. Haplotype-defining variants were verified in 203 patients with cancer, 582 relatives, and 42,438 newborns. The compound mutant haplotype was enriched in patients with cancer, conferring risk for sarcoma (P = 0.003) and subsequent malignancies (P = 0.006). Functional analyses demonstrated that wild-type XAF1 enhances transactivation of wild-type and hypomorphic TP53 variants, whereas XAF1-E134* is markedly attenuated in this activity. We propose that cosegregation of XAF1-E134* and TP53-R337H mutations leads to a more aggressive cancer phenotype than TP53-R337H alone, with implications for genetic counseling and clinical management of hypomorphic TP53 mutant carriers.

The prevailing explanation for Neanderthal body form is the cold (glacial) adaptation hypothesis. However, palaeoecological associations appear to indicate a less cold woodland environment. Under such conditions, encounter and ambush (rather than pursuit) hunting – and thus muscular power and sprint (rather than endurance) capacity – would have been favoured. We hypothesise that the highly muscular Neanderthal body form reflects an adaptation to hunting conditions rather than cold, and here both review the palaeoecological evidence that they inhabited a mainly woodland environment, and present preliminary genetic analyses in support of this new hypothesis.

Individuals harboring a germline TP53 mutation have a high lifetime risk of a broad spectrum of cancers, but the age of onset, tumor types and penetrance vary among carriers. The TP53-R337H variant is common in South and Southeastern Brazil due to founder effect and detected in 0.3% of the general population. TP53-R337H predisposes children to adrenocortical tumors (ACTs) and adults to various other Li-Fraumeni syndrome (LFS)-associated core cancers. Assessment of the family history of cancer in TP53-R337H carriers has revealed families fulfilling the classic criteria for LFS as well as those showing an apparently sporadic pattern of cancer presentation, suggesting that genetic and/or environmental factors modulate cancer penetrance in TP53-R337H carriers. Given the incomplete penetrance and heterogeneous familial cancer pattern in TP53-R337H carriers, we hypothesized that additional allelic variants in cis could act as modifiers of TP53-R337H activity and contribute to cancer risk. We used whole genome sequencing for fine mapping analysis of 2-Mb region flanking TP53 locus in ACT samples. Selected common and rare variants were genotyped in 204 unrelated TP53-R337H cancer patients and a control group of 67,359 newborns. Segregation analysis was performed by analyzing 682 family members. Cancer risk was ascertained, and in-vitro functional analysis was performed. We identified a common shared haplotype containing the E134* variant in the XAF1 gene in a subset (42%) of ACT patients harboring the TP53-R337H mutation. This rare variant (minor allele frequency worldwide= 0.004) was identified in 70% of TP53-R337H carrying chromosomes. Co-segregation of both variants was observed in 79% of cancer patients, however, it was significantly enriched in individuals with sarcoma (odds ratio, 5.6; 95% CI, 1.3 to 50.8; P=0.010) and multiple primary malignancies (odds ratio, 3.1; 95% CI, 1.0 to 12.9; P=0.033). Breast cancer patients harboring the extended haplotype developed multiple primary tumors three times more frequently than patients with the TP53-R337H-only haplotype. In vitro studies demonstrated that wild-type XAF1 enhances wild-type and p53-R337H transactivation whereas XAF1-E134* markedly attenuated this activity, thereby establishing a functional interaction between p53 and XAF1. These findings demonstrate that a tolerated and common polymorphism (XAF1-E134*) cooperates with the low-penetrance TP53-R337H variant to modulate cancer phenotype and highlights the potential biological contribution of additional variants that act in cis to influence the cancer phenotype conferred by low-penetrance TP53 alleles. Understanding the nature of the germline TP53 mutation and the contribution of other modifiers that influence its function, such as XAF1-E134*, will have implications for genetic counseling, surveillance and clinical management of these patients. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

The roles of migration, admixture and acculturation in the European transition to farming have been debated for over 100 years. Genome-wide ancient DNA studies indicate predominantly Aegean ancestry for continental Neolithic farmers, but also variable admixture with local Mesolithic hunter-gatherers. Neolithic cultures first appear in Britain ca. 4000 BCE, a millennium after they appear in adjacent areas of continental Europe. The pattern and process of this delayed British Neolithic transition remains unclear. We assembled genome-wide data from six Mesolithic and 67 Neolithic individuals found in Britain, dating from 8500-2500 BCE. Our analyses reveal persistent genetic affinities between Mesolithic British and Western European hunter-gatherers. We find overwhelming support for agriculture being introduced to Britain by incoming continental farmers, with small, geographically-structured levels of hunter-gatherer ancestry. Unlike other European Neolithic populations, we detect no resurgence of hunter-gatherer ancestry at any time during the Neolithic in Britain. Genetic affinities with Iberian Neolithic individuals indicate that British Neolithic people were mostly descended from Aegean farmers who followed the Mediterranean route of dispersal. We also infer considerable variation in pigmentation levels in Europe by ca. 6000 BCE.

Summary The Rab family of small GTPases regulates and provides specificity to the endomembrane trafficking system; each Rab subfamily is associated with specific pathways. Thus, characterization of Rab repertoires provides functional information about organisms and evolution of the eukaryotic cell. Yet, the complex structure of the Rab family limits the application of existing methods for protein classification. Here, we present a major redesign of the Rabifier, a bioinformatic pipeline for detection and classification of Rab GTPases. It is more accurate, significantly faster than the original version and is now open source, both the code and the data, allowing for community participation. Availability and Implementation Rabifier and RabDB are freely available through the web at http://rabdb.org. The Rabifier package can be downloaded from the Python Package Index at https://pypi.python.org/pypi/rabifier, the source code is available at Github https://github.com/evocell/rabifier. Supplementary information Supplementary data are available at Bioinformatics online.

CHC22 clathrin plays a key role in intracellular membrane traffic of the insulin-responsive glucose transporter GLUT4 in humans. We performed population genetic and phylogenetic analyses of the CHC22-encoding CLTCL1 gene, revealing independent gene loss in at least two vertebrate lineages, after arising from gene duplication. All vertebrates retained the paralogous CLTC gene encoding CHC17 clathrin, which mediates endocytosis. For vertebrates retaining CLTCL1, strong evidence for purifying selection supports CHC22 functionality. All human populations maintained two high frequency CLTCL1 allelic variants, encoding either methionine or valine at position 1316. Functional studies indicated that CHC22-V1316, which is more frequent in farming populations than in hunter-gatherers, has different cellular dynamics than M1316-CHC22 and is less effective at controlling GLUT4 membrane traffic, altering its insulin-regulated response. These analyses suggest that ancestral human dietary change influenced selection of allotypes that affect CHC22’s role in metabolism and have potential to differentially influence the human insulin response., eLife digest When we eat carbohydrates, they are digested into sugars that circulate in the blood to provide energy for the brain and other parts of the body. But too much blood sugar can be poisonous. The body regulates blood sugar balance using the hormone insulin, which triggers the removal of sugar from the blood into muscle and fat cells. This removal process involves a pore in membranes at the surface of muscle and fat tissue, called a glucose transporter, through which the sugar molecules can pass. During fasting, the glucose transporter remains inside muscle and fat. But after a meal, insulin acts to release the transporter from its storage area to the surface of the tissue. How efficiently this process happens reflects how efficiently sugar can be removed from the blood. When this pathway breaks down, it can lead to diabetes. In humans, a protein called CHC22 is needed to deliver the glucose transporter to its storage area. In mice, CHC22 is absent. The question arises: do different animals' eating habits influence CHC22's role in controlling blood sugar? The evolutionary history of CHC22 in a number of different animals could reveal what is special about glucose transport after a meal in humans, and how it might fail in diabetes. By analyzing the genomes of several different species, Fumagalli et al. found that the gene encoding CHC22 first evolved around the time animals began developing a backbone and complex nervous systems. Afterwards, it was lost by some animals – including mice, sheep and pigs. Fumagalli et al. also discovered that CHC22 varies between individual people. A new form of CHC22, which first appeared in ancient humans, is less effective at holding the glucose transporter inside muscle and fat – leading to a tendency to reduce blood sugar levels. This new form became more common in humans over a period witnessing the introduction of cooking, and later farming; both of these technologies are associated with increased sugar in the diet. But not everyone has this new variant of the gene – both the old and newer variants are present in people today. The history of CHC22 suggests that it was useful for early humans to hold the glucose transporter inside muscle and fat, keeping blood sugar levels high, which contributed to the development of a large brain. But as humans became exposed to higher dietary levels of sugar the newer form of CHC22 allowed blood sugar to be lowered more readily. People with different forms of CHC22 are likely to differ in their ability to control blood sugar after a meal. In some cases, this could lead to heightened blood sugar levels, which in turn can lead to diabetes.

The roles of migration, admixture and acculturation in the European transition to farming have been debated for over 100 years. Genome-wide ancient DNA studies indicate predominantly Anatolian ancestry for continental Neolithic farmers, but also variable admixture with local Mesolithic hunter-gatherers1–9. Neolithic cultures first appear in Britain c. 6000 years ago (kBP), a millennium after they appear in adjacent areas of northwestern continental Europe. However, the pattern and process of the British Neolithic transition remains unclear10–15. We assembled genome-wide data from six Mesolithic and 67 Neolithic individuals found in Britain, dating from 10.5-4.5 kBP, a dataset that includes 22 newly reported individuals and the first genomic data from British Mesolithic hunter-gatherers. Our analyses reveals persistent genetic affinities between Mesolithic British and Western European hunter-gatherers over a period spanning Britain’s separation from continental Europe. We find overwhelming support for agriculture being introduced by incoming continental farmers, with small and geographically structured levels of additional hunter-gatherer introgression. We find genetic affinity between British and Iberian Neolithic populations indicating that British Neolithic people derived much of their ancestry from Anatolian farmers who originally followed the Mediterranean route of dispersal and likely entered Britain from northwestern mainland Europe.

The concept of maximal perfect haplotype blocks is introduced as a simple pattern allowing to identify genomic regions that show signatures of natural selection. The model is formally defined and a simple algorithm is presented to find all perfect haplotype blocks in a set of phased chromosome sequences. Application to three whole chromosomes from the 1000 genomes project phase 3 data set shows the potential of the concept as an effective approach for quick detection of selection in large sets of thousands of genomes.

Liddle syndrome is considered a rare Mendelian hypertension. We have previously described 3 reportedly unrelated families, native of an Italian area around the Strait of Messina, carrying the same mutation (βP617L) of the epithelial sodium channel. The aims of our study were (1) to evaluate whether a close genomic relationship exists between the 3 families through the analysis of mitochondrial DNA and Y chromosome; and (2) to quantify the genomic relatedness between the patients with Liddle syndrome belonging to the 3 families and assess the hypothesis of a mutation shared through identity by descent. HVRI (the hypervariable region I) of the mitochondrial DNA genome and the Y chromosome short tandem repeats profiles were analyzed in individuals of the 3 families. Genotyping 542 585 genome-wide single nucleotide polymorphisms was performed in all the patients with Liddle syndrome of the 3 families and some of their relatives. A panel of 780 healthy Italian adult samples typed for the same set of markers was used as controls. espite different lineages between the 3 families based on the analysis of mitochondrial DNA and Y chromosome, the 3 probands and their 6 affected relatives share the same ≈5 Mbp long haplotype which encompasses the mutant allele. Using an approach based on coalescent theory, we estimate that the 3 families inherited the mutant allele from a common ancestor ≈13 generations ago and that such an ancestor may have left ≈20 carriers alive today. The prevalence of Liddle syndrome in the region of origin of the 3 families may be much higher than that estimated worldwide.

In the version of this Article originally published, there were errors in the colour ordering of the legend in Fig. 5b, and in the positions of the target and surrogate populations in Fig. 5c. This has now been corrected. The conclusions of the study are in no way affected. The errors have been corrected in the HTML and PDF versions of the article.

Protein evolution is governed by processes that alter primary sequence but also the length of proteins. Protein length may change in different ways, but insertions, deletions and duplications are the most common. An optimal protein size is a trade-off between sequence extension, which may change protein stability or lead to acquisition of a new function, and shrinkage that decreases metabolic cost of protein synthesis. Despite the general tendency for length conservation across orthologous proteins, the propensity to accept insertions and deletions is heterogeneous along the sequence. For example, protein regions rich in repetitive peptide motifs are well known to extensively vary their length across species. Here, we analyze length conservation of coiled-coils, domains formed by an ubiquitous, repetitive peptide motif present in all domains of life, that frequently plays a structural role in the cell. We observed that, despite the repetitive nature, the length of coiled-coil domains is generally highly conserved throughout the tree of life, even when the remaining parts of the protein change, including globular domains. Length conservation is independent of primary amino acid sequence variation, and represents a conservation of domain physical size. This suggests that the conservation of domain size is due to functional constraints.

The aryl hydrocarbon receptor interacting protein (AIP) founder mutation R304* (or p.R304*; NM_003977.3:c.910C>T, p.Arg304Ter) identified in Northern Ireland (NI) predisposes to acromegaly/gigantism; its population health impact remains unexplored. We measured R304* carrier frequency in 936 Mid Ulster, 1000 Greater Belfast (both in NI) and 2094 Republic of Ireland (ROI) volunteers and in 116 acromegaly/gigantism patients. Carrier frequencies were 0.0064 in Mid Ulster (95%CI = 0.0027-0.013; P = 0.0005 vs. ROI), 0.001 in Greater Belfast (0.00011-0.0047) and zero in ROI (0-0.0014). R304* prevalence was elevated in acromegaly/gigantism patients in NI (11/87, 12.6%, P < 0.05), but not in ROI (2/29, 6.8%) vs. non-Irish patients (0-2.41%). Haploblock conservation supported a common ancestor for all the 18 identified Irish pedigrees (81 carriers, 30 affected). Time to most recent common ancestor (tMRCA) was 2550 (1275-5000) years. tMRCA-based simulations predicted 432 (90-5175) current carriers, including 86 affected (18-1035) for 20% penetrance. In conclusion, R304* is frequent in Mid Ulster, resulting in numerous acromegaly/gigantism cases. tMRCA is consistent with historical/folklore accounts of Irish giants. Forward simulations predict many undetected carriers; geographically-targeted population screening improves asymptomatic carrier identification, complementing clinical testing of patients/relatives. We generated disease awareness locally, necessary for early diagnosis and improved outcomes of AIP-related disease. This article is protected by copyright. All rights reserved.

Precise estimation of age is essential in evolutionary anthropology, especially to infer population age structures and understand the evolution of human life history diversity. However, in small-scale societies, such as hunter-gatherer populations, time is often not referred to in calendar years, and accurate age estimation remains a challenge. We address this issue by proposing a Bayesian approach that accounts for age uncertainty inherent to fieldwork data. We developed a Gibbs sampling Markov chain Monte Carlo algorithm that produces posterior distributions of ages for each individual, based on a ranking order of individuals from youngest to oldest and age ranges for each individual. We first validate our method on 65 Agta foragers from the Philippines with known ages, and show that our method generates age estimations that are superior to previously published regression-based approaches. We then use data on 587 Agta collected during recent fieldwork to demonstrate how multiple partial age ranks coming from multiple camps of hunter-gatherers can be integrated. Finally, we exemplify how the distributions generated by our method can be used to estimate important demographic parameters in small-scale societies: here, age-specific fertility patterns. Our flexible Bayesian approach will be especially useful to improve cross-cultural life history datasets for small-scale societies for which reliable age records are difficult to acquire.

Objective Mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are associated with pituitary adenoma, acromegaly and gigantism. Identical alleles in unrelated pedigrees could be inherited from a common ancestor or result from recurrent mutation events. Design and methods Observational, inferential and experimental study, including: AIP mutation testing; reconstruction of 14 AIP-region (8.3 Mbp) haplotypes; coalescent-based approximate Bayesian estimation of the time to most recent common ancestor (tMRCA) of the derived allele; forward population simulations to estimate current number of allele carriers; proposal of mutation mechanism; protein structure predictions; co-immunoprecipitation and cycloheximide chase experiments. Results Nine European-origin, unrelated c.805_825dup-positive pedigrees (four familial, five sporadic from the UK, USA and France) included 16 affected (nine gigantism/four acromegaly/two non-functioning pituitary adenoma patients and one prospectively diagnosed acromegaly patient) and nine unaffected carriers. All pedigrees shared a 2.79 Mbp haploblock around AIP with additional haploblocks privately shared between subsets of the pedigrees, indicating the existence of an evolutionarily recent common ancestor, the ‘English founder’, with an estimated median tMRCA of 47 generations (corresponding to 1175 years) with a confidence interval (9–113 generations, equivalent to 225–2825 years). The mutation occurred in a small tandem repeat region predisposed to slipped strand mispairing. The resulting seven amino-acid duplication disrupts interaction with HSP90 and leads to a marked reduction in protein stability. Conclusions The c.805_825dup allele, originating from a common ancestor, associates with a severe clinical phenotype and a high frequency of gigantism. The mutation is likely to be the result of slipped strand mispairing and affects protein–protein interactions and AIP protein stability.

Objective Mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are associated with pituitary adenoma, acromegaly and gigantism. Identical alleles in unrelated pedigrees could be inherited from a common ancestor or result from recurrent mutation events. Design and methods Observational, inferential and experimental study, including: AIP mutation testing; reconstruction of 14 AIP-region (8.3 Mbp) haplotypes; coalescent-based approximate Bayesian estimation of the time to most recent common ancestor (tMRCA) of the derived allele; forward population simulations to estimate current number of allele carriers; proposal of mutation mechanism; protein structure predictions; co-immunoprecipitation and cycloheximide chase experiments. Results Nine European-origin, unrelated c.805_825dup-positive pedigrees (four familial, five sporadic from the UK, USA and France) included 16 affected (nine gigantism/four acromegaly/two non-functioning pituitary adenoma patients and one prospectively diagnosed acromegaly patient) and nine unaffected carriers. All pedigrees shared a 2.79 Mbp haploblock around AIP with additional haploblocks privately shared between subsets of the pedigrees, indicating the existence of an evolutionarily recent common ancestor, the ‘English founder’, with an estimated median tMRCA of 47 generations (corresponding to 1175 years) with a confidence interval (9–113 generations, equivalent to 225–2825 years). The mutation occurred in a small tandem repeat region predisposed to slipped strand mispairing. The resulting seven amino-acid duplication disrupts interaction with HSP90 and leads to a marked reduction in protein stability. Conclusions The c.805_825dup allele, originating from a common ancestor, associates with a severe clinical phenotype and a high frequency of gigantism. The mutation is likely to be the result of slipped strand mispairing and affects protein–protein interactions and AIP protein stability.

Bell Beaker pottery spread across western and central Europe beginning around 2750 BCE before disappearing between 2200–1800 BCE. The mechanism of its expansion is a topic of long-standing debate, with support for both cultural diffusion and human migration. We present new genome-wide ancient DNA data from 170 Neolithic, Copper Age and Bronze Age Europeans, including 100 Beaker-associated individuals. In contrast to the Corded Ware Complex, which has previously been identified as arriving in central Europe following migration from the east, we observe limited genetic affinity between Iberian and central European Beaker Complex-associated individuals, and thus exclude migration as a significant mechanism of spread between these two regions. However, human migration did have an important role in the further dissemination of the Beaker Complex, which we document most clearly in Britain using data from 80 newly reported individuals dating to 3900–1200 BCE. British Neolithic farmers were genetically similar to contemporary populations in continental Europe and in particular to Neolithic Iberians, suggesting that a portion of the farmer ancestry in Britain came from the Mediterranean rather than the Danubian route of farming expansion. Beginning with the Beaker period, and continuing through the Bronze Age, all British individuals harboured high proportions of Steppe ancestry and were genetically closely related to Beaker-associated individuals from the Lower Rhine area. We use these observations to show that the spread of the Beaker Complex to Britain was mediated by migration from the continent that replaced >90% of Britain’s Neolithic gene pool within a few hundred years, continuing the process that brought Steppe ancestry into central and northern Europe 400 years earlier.

WOS: 000378272400038, PubMed ID: 27274049, Farming and sedentism first appeared in southwestern Asia during the early Holocene and later spread to neighboring regions, including Europe, along multiple dispersal routes. Conspicuous uncertainties remain about the relative roles of migration, cultural diffusion, and admixture with local foragers in the early Neolithization of Europe. Here we present paleogenomic data for five Neolithic individuals from northern Greece and northwestern Turkey spanning the time and region of the earliest spread of farming into Europe. We use a novel approach to recalibrate raw reads and call genotypes from ancient DNA and observe striking genetic similarity both among Aegean early farmers and with those from across Europe. Our study demonstrates a direct genetic link between Mediterranean and Central European early farmers and those of Greece and Anatolia, extending the European Neolithic migratory chain all the way back to southwestern Asia., Marie Curie Initial Training Network (BEAN/Bridging the European and Anatolian Neolithic) [GA 289966]; DFGGerman Research Foundation (DFG) [BU 1403/6-1, BO 4119/1]; Alexander von Humboldt FoundationAlexander von Humboldt Foundation; European Union (EU) SYNTHESYS/Synthesis of Systematic Resources [GA 226506-CP-CSA-INFRA]; VolkswagenstiftungVolkswagen [FKZ: 87161]; Irish Research CouncilIrish Research Council for Science, Engineering and Technology [GOIPG/2013/1219]; EU CodeX Project [295729]; EU Social Fund; Greek national funds research funding program THALES; Greek national funds research funding program ARISTEIA II; Swiss NSFSwiss National Science Foundation (SNSF) [31003A_156853, 31003A_149920]; BBSRCBiotechnology and Biological Sciences Research Council (BBSRC) [BB/L009382/1]; CoMPLEX via EPSRC [EP/F500351/1]; Sir Henry Dale Fellowship - Wellcome Trust [098386/Z/12/Z]; Sir Henry Dale Fellowship - Royal Society [098386/Z/12/Z]; National Institute for Health Research University College London Hospitals Biomedical Research Centre; Wellcome TrustWellcome Trust [100719/Z/12/Z]; University of Mainz; HPC cluster MOGON - DFG [INST 247/602-1 FUGG]; Netherlands Organization for Scientific ResearchNetherlands Organization for Scientific Research (NWO) [380-62-005]; Biotechnology and Biological Sciences Research CouncilBiotechnology and Biological Sciences Research Council (BBSRC) [BB/L009382/1]; Engineering and Physical Sciences Research CouncilEngineering & Physical Sciences Research Council (EPSRC) [1357822], We thank Songul Alpaslan for help with sampling in Barcin and Eleni Stravopodi for help with sampling in Theopetra. Z.H. and R.M. are supported by a Marie Curie Initial Training Network (BEAN/Bridging the European and Anatolian Neolithic, GA 289966) awarded to M.C., S.J.S., D.G.B., M.G.T., and J. Burger. C.P., J. Burger and S.K. received funding from DFG (BU 1403/6-1). C.P. and J. Burger received funding from the Alexander von Humboldt Foundation. C.S. and M.S. were supported by the European Union (EU) SYNTHESYS/Synthesis of Systematic Resources GA 226506-CP-CSA-INFRA, DFG: (BO 4119/1) and Volkswagenstiftung (FKZ: 87161). L.M.C. is funded by the Irish Research Council (GOIPG/2013/1219). A.S. was supported by the EU CodeX Project 295729. K. Kotsakis, S.T., D.U.-K., P.H., and C.P. were cofinanced by the EU Social Fund and Greek national funds research funding program THALES. C.P., M.U., K. Kotsakis, S.T., and D.U.-K. were cofinanced by the EU Social Fund and the Greek national funds research funding program ARISTEIA II. M.C. was supported by Swiss NSF Grant 31003A_156853. A. K. and D.W. were supported by Swiss NSF Grant 31003A_149920. S.L. is supported by the BBSRC (Grant BB/L009382/1). L.v.D. is supported by CoMPLEX via EPSRC (Grant EP/F500351/1). G.H. is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant 098386/Z/12/Z) and by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. M.G.T. and Y.D. are supported by a Wellcome Trust Senior Research Fellowship Grant 100719/Z/12/Z (to M.G.T.). J. Burger is grateful for support by the University of Mainz and the HPC cluster MOGON (funded by DFG; INST 247/602-1 FUGG). F.G. was supported by Grant 380-62-005 of the Netherlands Organization for Scientific Research.

Protein evolution is governed by processes that alter primary sequence but also the length of proteins. Protein length may change in different ways, but insertions, deletions and duplications are the most common. An optimal protein size is a trade-off between sequence extension, which may change protein stability or lead to acquisition of a new function, and shrinkage that decreases metabolic cost of protein synthesis. Despite the general tendency for length conservation across orthologous proteins, the propensity to accept insertions and deletions is heterogeneous along the sequence. For example, protein regions rich in repetitive peptide motifs are well known to extensively vary their length across species. Here, we analyze length conservation of coiled-coils, domains formed by an ubiquitous, repetitive peptide motif present in all domains of life, that frequently plays a structural role in the cell. We observed that, despite the repetitive nature, the length of coiled-coil domains is generally highly conserved throughout the tree of life, even when the remaining parts of the protein change, including globular domains. Length conservation is independent of primary amino acid sequence variation, and represents a conservation of domain physical size. This suggests that the conservation of domain size is due to functional constraints.

The bioinformatic annotation of Rab GTPases is important, for example, to understand the evolution of the endomembrane system. However, Rabs are particularly challenging for standard annotation pipelines because they are similar to other small GTPases and form a large family with many paralogous subfamilies. Here, we describe a bioinformatic annotation pipeline specifically tailored to Rab GTPases. It proceeds in two steps: first, Rabs are distinguished from other proteins based on GTPase-specific motifs, overall sequence similarity to other Rabs, and the occurrence of Rab-specific motifs. Second, Rabs are classified taking either a more accurate but slower phylogenetic approach or a slightly less accurate but much faster bioinformatic approach. All necessary steps can either be performed locally or using the referenced online tools. An implementation of a slightly more involved version of the pipeline presented here is available at RabDB.org.

The deposited article version is a "MBE Advance Access" published on March 4, 2015" provided by Oxford University Press, and it contains attached the supplementary materials within the pdf. The deposited article is a post-print version. Some supplementary materials are not present in the uploaded version of the article. Gene families often consist of members with diverse expression domains reflecting their functions in a wide variety of tissues. However, how the expression of individual members, and thus their tissue-specific functions, diversified during the course of gene family expansion is not well understood. In this study, we approached this question through the analysis of the duplication history and transcriptional evolution of a rapidly expanding subfamily of insect Ly6 genes. We analyzed different insect genomes and identified seven Ly6 genes that have originated from a single ancestor through sequential duplication within the higher Diptera. We then determined how the original embryonic expression pattern of the founding gene diversified by characterizing its tissue-specific expression in the beetle Tribolium castaneum, the butterfly Bicyclus anynana, and the mosquito Anopheles stephensi and those of its duplicates in three higher dipteran species, representing various stages of the duplication history (Megaselia abdita, Ceratitis capitata, and Drosophila melanogaster). Our results revealed that frequent neofunctionalization episodes contributed to the increased expression breadth of this subfamily and that these events occurred after duplication and speciation events at comparable frequencies. In addition, at each duplication node, we consistently found asymmetric expression divergence. One paralog inherited most of the tissue-specificities of the founder gene, whereas the other paralog evolved drastically reduced expression domains. Our approach attests to the power of combining a well-established duplication history with a comprehensive coverage of representative species in acquiring unequivocal information about the dynamics of gene expression evolution in gene families. IAEA Seibersdorf (Austria); USDA; Duke University; McGill University; DRGC (Kyoto); DSHB (Iowa); Toulouse RIO Imaging Platform; Fundação para a Ciência e a Tecnologia grants: (SFRH/BPD/75139/2010, ANR-13-ISV7-0001-01, ANR-13-ISV7-0001-02, FCT-ANR/BIA-ANM/0003/2013); Fundação Calouste Gulbenkian; Instituto Gulbenkian de Ciência; Agence Nationale de la Recherche (ANR). info:eu-repo/semantics/publishedVersion

The bioinformatic annotation of Rab GTPases is important, for example, to understand the evolution of the endomembrane system. However, Rabs are particularly challenging for standard annotation pipelines because they are similar to other small GTPases and form a large family with many paralogous subfamilies. Here, we describe a bioinformatic annotation pipeline specifically tailored to Rab GTPases. It proceeds in two steps: first, Rabs are distinguished from other proteins based on GTPase-specific motifs, overall sequence similarity to other Rabs, and the occurrence of Rab-specific motifs. Second, Rabs are classified taking either a more accurate but slower phylogenetic approach or a slightly less accurate but much faster bioinformatic approach. All necessary steps can either be performed locally or using the referenced online tools. An implementation of a slightly more involved version of the pipeline presented here is available at RabDB.org.

Cells compartmentalize their biochemical functions in a variety of ways, notably by creating physical barriers that separate a compartment via membranes or proteins. Eukaryotes have a wide diversity of membrane-based compartments, many that are lineage- or tissue-specific. In recent years, it has become increasingly evident that membrane-based compartmentalization of the cytosolic space is observed in multiple prokaryotic lineages, giving rise to several types of distinct prokaryotic organelles. Endosymbionts, previously believed to be a hallmark of eukaryotes, have been described in several bacteria. Protein-based compartments, frequent in bacteria, are also found in eukaryotes. In the present review, we focus on selected intracellular compartments from each of these three categories, membrane-based, endosymbiotic and protein-based, in both prokaryotes and eukaryotes. We review their diversity and the current theories and controversies regarding the evolutionary origins. Furthermore, we discuss the evolutionary processes acting on the genetic basis of intracellular compartments and how those differ across the domains of life. We conclude that the distinction between eukaryotes and prokaryotes no longer lies in the existence of a compartmentalized cell plan, but rather in its complexity.

In comparative genomics, gene order data is often modeled as signed permutations. A classical problem for genome comparison is to detect common intervals in permutations, that is, genes that are colocalized in several species, indicating that they remained grouped during evolution. A second largely studied problem related to gene order is to compute a minimum scenario of reversals that transforms a signed permutation into another. Several studies began to mix the two problems and it was observed that their results are not always compatible: Often, parsimonious scenarios of reversals break common intervals. If a scenario does not break any common interval, it is called perfect. In two recent studies, Bérard et al. defined a class of permutations for which building a perfect scenario of reversals sorting a permutation was achieved in polynomial time and stated as an open question whether it is possible to decide, given a permutation, if there exists a minimum scenario of reversals that is perfect. In this paper, we give a solution to this problem and prove that this widens the class of permutations addressed by the aforementioned studies. We implemented and tested this algorithm on gene order data of chromosomes from several mammal species and we compared it to other methods. The algorithm helps to choose among several possible scenarios of reversals and indicates that the minimum scenario of reversals is not always the most plausible.