A noncoding regulatory variant in IKZF1 increases acute lymphoblastic leukemia risk in Hispanic/Latino children.

Hispanic/Latino children have the highest risk of acute lymphoblastic leukemia (ALL) in the US compared to other racial/ethnic groups, yet the basis of this remains incompletely understood. Through genetic fine-mapping analyses, we identified a new independent childhood ALL risk signal near IKZF1 in self-reported Hispanic/Latino individuals, but not in non-Hispanic White individuals, with an effect size of ∼1.44 (95% confidence interval = 1.33-1.55) and a risk allele frequency of ∼18% in Hispanic/Latino populations and <0.5% in European populations. This risk allele was positively associated with Indigenous American ancestry, showed evidence of selection in human history, and was associated with reduced IKZF1 expression. We identified a putative causal variant in a downstream enhancer that is most active in pro-B cells and interacts with the IKZF1 promoter. This variant disrupts IKZF1 autoregulation at this enhancer and results in reduced enhancer activity in B cell progenitors. Our study reveals a genetic basis for the increased ALL risk in Hispanic/Latino children.

Recombination map tailored to Native Hawaiians may improve robustness of genomic scans for positive selection.

Recombination events establish the patterns of haplotypic structure in a population and estimates of recombination rates are used in several downstream population and statistical genetic analyses. Using suboptimal maps from distantly related populations may reduce the efficacy of genomic analyses, particularly for underrepresented populations such as the Native Hawaiians. To overcome this challenge, we constructed recombination maps using genome-wide array data from two study samples of Native Hawaiians: one reflecting the current admixed state of Native Hawaiians (NH map) and one based on individuals of enriched Polynesian ancestries (PNS map) with the potential to be used for less admixed Polynesian populations such as the Samoans. We found the recombination landscape to be less correlated with those from other continental populations (e.g. Spearman's rho = 0.79 between PNS and CEU (Utah residents with Northern and Western European ancestry) compared to 0.92 between YRI (Yoruba in Ibadan, Nigeria) and CEU at 50 kb resolution), likely driven by the unique demographic history of the Native Hawaiians. PNS also shared the fewest recombination hotspots with other populations (e.g. 8% of hotspots shared between PNS and CEU compared to 27% of hotspots shared between YRI and CEU). We found that downstream analyses in the Native Hawaiian population, such as local ancestry inference, imputation, and IBD segment and relatedness detections, would achieve similar efficacy when using the NH map compared to an omnibus map. However, for genome scans of adaptive loci using integrated haplotype scores, we found several loci with apparent genome-wide significant signals (|Z-score|> 4) in Native Hawaiians that would not have been significant when analyzed using NH-specific maps. Population-specific recombination maps may therefore improve the robustness of haplotype-based statistics and help us better characterize the evolutionary history that may underlie Native Hawaiian-specific health conditions that persist today.

Genetic continuity and change among the Indigenous peoples of California.

Before the colonial period, California harboured more language variation than all of Europe, and linguistic and archaeological analyses have led to many hypotheses to explain this diversity1. We report genome-wide data from 79 ancient individuals from California and 40 ancient individuals from Northern Mexico dating to 7,400-200 years before present (BP). Our analyses document long-term genetic continuity between people living on the Northern Channel Islands of California and the adjacent Santa Barbara mainland coast from 7,400 years BP to modern Chumash groups represented by individuals who lived around 200 years BP. The distinctive genetic lineages that characterize present-day and ancient people from Northwest Mexico increased in frequency in Southern and Central California by 5,200 years BP, providing evidence for northward migrations that are candidates for spreading Uto-Aztecan languages before the dispersal of maize agriculture from Mexico2-4. Individuals from Baja California share more alleles with the earliest individual from Central California in the dataset than with later individuals from Central California, potentially reflecting an earlier linguistic substrate, whose impact on local ancestry was diluted by later migrations from inland regions1,5. After 1,600 years BP, ancient individuals from the Channel Islands lived in communities with effective sizes similar to those in pre-agricultural Caribbean and Patagonia, and smaller than those on the California mainland and in sampled regions of Mexico.

Recombination map tailored to Native Hawaiians improves robustness of genomic scans for positive selection.

Recombination events establish the patterns of haplotypic structure in a population and estimates of recombination rates are used in several downstream population and statistical genetic analyses. Using suboptimal maps from distantly related populations may reduce the efficacy of genomic analyses, particularly for underrepresented populations such as the Native Hawaiians. To overcome this challenge, we constructed recombination maps using genome-wide array data from two study samples of Native Hawaiians: one reflecting the current admixed state of Native Hawaiians (NH map), and one based on individuals of enriched Polynesian ancestries (PNS map) with the potential to be used for less admixed Polynesian populations such as the Samoans. We found the recombination landscape to be less correlated with those from other continental populations (e.g. Spearman's rho = 0.79 between PNS and CEU (Utah residents with Northern and Western European ancestry) compared to 0.92 between YRI (Yoruba in Ibadan, Nigeria) and CEU at 50 kb resolution), likely driven by the unique demographic history of the Native Hawaiians. PNS also shared the fewest recombination hotspots with other populations (e.g. 8% of hotspots shared between PNS and CEU compared to 27% of hotspots shared between YRI and CEU). We found that downstream analyses in the Native Hawaiian population, such as local ancestry inference, imputation, and IBD segment and relatedness detections, would achieve similar efficacy when using the NH map compared to an omnibus map. However, for genome scans of adaptive loci using integrated haplotype scores, we found several loci with apparent genome-wide significant signals (|Z-score| > 4) in Native Hawaiians that would not have been significant when analyzed using NH-specific maps. Population-specific recombination maps may therefore improve the robustness of haplotype-based statistics and help us better characterize the evolutionary history that may underlie Native Hawaiian-specific health conditions that persist today.

The accuracy of polygenic score models for anthropometric traits and Type II Diabetes in the Native Hawaiian Population.

Polygenic scores (PGS) are promising in stratifying individuals based on the genetic susceptibility to complex diseases or traits. However, the accuracy of PGS models, typically trained in European- or East Asian-ancestry populations, tend to perform poorly in other ethnic minority populations, and their accuracies have not been evaluated for Native Hawaiians. Using body mass index, height, and type-2 diabetes as examples of highly polygenic traits, we evaluated the prediction accuracies of PGS models in a large Native Hawaiian sample from the Multiethnic Cohort with up to 5,300 individuals. We evaluated both publicly available PGS models or genome-wide PGS models trained in this study using the largest available GWAS. We found evidence of lowered prediction accuracies for the PGS models in some cases, particularly for height. We also found that using the Native Hawaiian samples as an optimization cohort during training did not consistently improve PGS performance. Moreover, even the best performing PGS models among Native Hawaiians would have lowered prediction accuracy among the subset of individuals most enriched with Polynesian ancestry. Our findings indicate that factors such as admixture histories, sample size and diversity in GWAS can influence PGS performance for complex traits among Native Hawaiian samples. This study provides an initial survey of PGS performance among Native Hawaiians and exposes the current gaps and challenges associated with improving polygenic prediction models for underrepresented minority populations.

Ethics of DNA research on human remains: five globally applicable guidelines.

We are a group of archaeologists, anthropologists, curators and geneticists representing diverse global communities and 31 countries. All of us met in a virtual workshop dedicated to ethics in ancient DNA research held in November 2020. There was widespread agreement that globally applicable ethical guidelines are needed, but that recent recommendations grounded in discussion about research on human remains from North America are not always generalizable worldwide. Here we propose the following globally applicable guidelines, taking into consideration diverse contexts. These hold that: (1) researchers must ensure that all regulations were followed in the places where they work and from which the human remains derived; (2) researchers must prepare a detailed plan prior to beginning any study; (3) researchers must minimize damage to human remains; (4) researchers must ensure that data are made available following publication to allow critical re-examination of scientific findings; and (5) researchers must engage with other stakeholders from the beginning of a study and ensure respect and sensitivity to stakeholder perspectives. We commit to adhering to these guidelines and expect they will promote a high ethical standard in DNA research on human remains going forward.

Ancient genomes reveal long-range influence of the pre-Columbian culture and site of Tiwanaku.

Tiwanaku civilization flourished in the Lake Titicaca basin between 500 and 1000 CE and at its apogee influenced wide areas across the southern Andes. Despite a considerable amount of archaeological data, little is known about the Tiwanaku population. We analyzed 17 low-coverage genomes from individuals dated between 300 and 1500 CE and demonstrated genetic continuity in the Lake Titicaca basin throughout this period, which indicates that the substantial cultural and political changes in the region were not accompanied by large-scale population movements. Conversely, the ritual center of Tiwanaku revealed high diversity, including individuals with primarily local genetic ancestry and those with foreign admixture or provenance from as far as the Amazon. Nonetheless, most human offerings associated with the Akapana platform exhibited pure Titicaca basin ancestry and dated to ca. 950 CE­the onset of Tiwanaku's decline as a sociopolitical center. Our results strengthen the view of Tiwanaku as a complex and far-reaching polity.

Two genetic variants explain the association of European ancestry with multiple sclerosis risk in African-Americans.

Epidemiological studies have suggested differences in the rate of multiple sclerosis (MS) in individuals of European ancestry compared to African ancestry, motivating genetic scans to identify variants that could contribute to such patterns. In a whole-genome scan in 899 African-American cases and 1155 African-American controls, we confirm that African-Americans who inherit segments of the genome of European ancestry at a chromosome 1 locus are at increased risk for MS [logarithm of odds (LOD) = 9.8], although the signal weakens when adding an additional 406 cases, reflecting heterogeneity in the two sets of cases [logarithm of odds (LOD) = 2.7]. The association in the 899 individuals can be fully explained by two variants previously associated with MS in European ancestry individuals. These variants tag a MS susceptibility haplotype associated with decreased CD58 gene expression (odds ratio of 1.37; frequency of 84% in Europeans and 22% in West Africans for the tagging variant) as well as another haplotype near the FCRL3 gene (odds ratio of 1.07; frequency of 49% in Europeans and 8% in West Africans). Controlling for all other genetic and environmental factors, the two variants predict a 1.44-fold higher rate of MS in European-Americans compared to African-Americans.

Ancient genomes in South Patagonia reveal population movements associated with technological shifts and geography.

Archaeological research documents major technological shifts among people who have lived in the southern tip of South America (South Patagonia) during the last thirteen millennia, including the development of marine-based economies and changes in tools and raw materials. It has been proposed that movements of people spreading culture and technology propelled some of these shifts, but these hypotheses have not been tested with ancient DNA. Here we report genome-wide data from 20 ancient individuals, and co-analyze it with previously reported data. We reveal that immigration does not explain the appearance of marine adaptations in South Patagonia. We describe partial genetic continuity since ~6600 BP and two later gene flows correlated with technological changes: one between 4700-2000 BP that affected primarily marine-based groups, and a later one impacting all <2000 BP groups. From ~2200-1200 BP, mixture among neighbors resulted in a cline correlated to geographic ordering along the coast.

ContamLD: estimation of ancient nuclear DNA contamination using breakdown of linkage disequilibrium.

We report a method called ContamLD for estimating autosomal ancient DNA (aDNA) contamination by measuring the breakdown of linkage disequilibrium in a sequenced individual due to the introduction of contaminant DNA. ContamLD leverages the idea that contaminants should have haplotypes uncorrelated to those of the studied individual. Using simulated data, we confirm that ContamLD accurately infers contamination rates with low standard errors: for example, less than 1.5% standard error in cases with less than 10% contamination and 500,000 sequences covering SNPs. This method is optimized for application to aDNA, taking advantage of characteristic aDNA damage patterns to provide calibrated contamination estimates, and is available at https://github.com/nathan-nakatsuka/ContamLD .

Integration of ancient DNA with transdisciplinary dataset finds strong support for Inca resettlement in the south Peruvian coast.

Ancient DNA (aDNA) analysis provides a powerful means of investigating human migration, social organization, and a plethora of other crucial questions about humanity's past. Recently, specialists have suggested that the ideal research design involving aDNA would include multiple independent lines of evidence. In this paper, we adopt a transdisciplinary approach integrating aDNA with archaeological, biogeochemical, and historical data to investigate six individuals found in two cemeteries that date to the Late Horizon (1400 to 1532 CE) and Colonial (1532 to 1825 CE) periods in the Chincha Valley of southern Peru. Genomic analyses indicate that these individuals are genetically most similar to ancient and present-day populations from the north Peruvian coast located several hundred kilometers away. These genomic data are consistent with 16th century written records as well as ceramic, textile, and isotopic data. These results provide some of the strongest evidence yet of state-sponsored resettlement in the pre-Colonial Andes. This study highlights the power of transdisciplinary research designs when using aDNA data and sets a methodological standard for investigating ancient mobility in complex societies.

A Paleogenomic Reconstruction of the Deep Population History of the Andes.

There are many unanswered questions about the population history of the Central and South Central Andes, particularly regarding the impact of large-scale societies, such as the Moche, Wari, Tiwanaku, and Inca. We assembled genome-wide data on 89 individuals dating from ∼9,000-500 years ago (BP), with a particular focus on the period of the rise and fall of state societies. Today's genetic structure began to develop by 5,800 BP, followed by bi-directional gene flow between the North and South Highlands, and between the Highlands and Coast. We detect minimal admixture among neighboring groups between ∼2,000-500 BP, although we do detect cosmopolitanism (people of diverse ancestries living side-by-side) in the heartlands of the Tiwanaku and Inca polities. We also highlight cases of long-range mobility connecting the Andes to Argentina and the Northwest Andes to the Amazon Basin. VIDEO ABSTRACT.

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

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.

The formation of human populations in South and Central Asia.

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.

Reconstructing the Deep Population History of Central and South America.

We report genome-wide ancient DNA from 49 individuals forming four parallel time transects in Belize, Brazil, the Central Andes, and the Southern Cone, each dating to at least ∼9,000 years ago. The common ancestral population radiated rapidly from just one of the two early branches that contributed to Native Americans today. We document two previously unappreciated streams of gene flow between North and South America. One affected the Central Andes by ∼4,200 years ago, while the other explains an affinity between the oldest North American genome associated with the Clovis culture and the oldest Central and South Americans from Chile, Brazil, and Belize. However, this was not the primary source for later South Americans, as the other ancient individuals derive from lineages without specific affinity to the Clovis-associated genome, suggesting a population replacement that began at least 9,000 years ago and was followed by substantial population continuity in multiple regions.

The promise of discovering population-specific disease-associated genes in South Asia.

The more than 1.5 billion people who live in South Asia are correctly viewed not as a single large population but as many small endogamous groups. We assembled genome-wide data from over 2,800 individuals from over 260 distinct South Asian groups. We identified 81 unique groups, 14 of which had estimated census sizes of more than 1 million, that descend from founder events more extreme than those in Ashkenazi Jews and Finns, both of which have high rates of recessive disease due to founder events. We identified multiple examples of recessive diseases in South Asia that are the result of such founder events. This study highlights an underappreciated opportunity for decreasing disease burden among South Asians through discovery of and testing for recessive disease-associated genes.

CLYBL is a polymorphic human enzyme with malate synthase and ß-methylmalate synthase activity.

CLYBL is a human mitochondrial enzyme of unknown function that is found in multiple eukaryotic taxa and conserved to bacteria. The protein is expressed in the mitochondria of all mammalian organs, with highest expression in brown fat and kidney. Approximately 5% of all humans harbor a premature stop polymorphism in CLYBL that has been associated with reduced levels of circulating vitamin B12. Using comparative genomics, we now show that CLYBL is strongly co-expressed with and co-evolved specifically with other components of the mitochondrial B12 pathway. We confirm that the premature stop polymorphism in CLYBL leads to a loss of protein expression. To elucidate the molecular function of CLYBL, we used comparative operon analysis, structural modeling and enzyme kinetics. We report that CLYBL encodes a malate/ß-methylmalate synthase, converting glyoxylate and acetyl-CoA to malate, or glyoxylate and propionyl-CoA to ß-methylmalate. Malate synthases are best known for their established role in the glyoxylate shunt of plants and lower organisms and are traditionally described as not occurring in humans. The broader role of a malate/ß-methylmalate synthase in human physiology and its mechanistic link to vitamin B12 metabolism remain unknown.

Factors influencing the degradation of archival formalin-fixed paraffin-embedded tissue sections.

The loss of antigenicity in archival formalin-fixed paraffin-embedded (FFPE) tissue sections negatively affects both diagnostic histopathology and advanced molecular studies. The mechanisms underlying antigenicity loss in FFPE tissues remain unclear. The authors hypothesize that water is a crucial contributor to protein degradation and decrement of immunoreactivity in FFPE tissues. To test their hypothesis, they examined fixation time, processing time, and humidity of storage environment on protein integrity and antigenicity by immunohistochemistry, Western blotting, and protein extraction. This study revealed that inadequate tissue processing, resulting in retention of endogenous water in tissue sections, results in antigen degradation. Exposure to high humidity during storage results in significant protein degradation and reduced immunoreactivity, and the effects of storage humidity are temperature dependent. Slides stored under vacuum with desiccant do not protect against the effects of residual water from inadequate tissue processing. These results support that the presence of water, both endogenously and exogenously, plays a central role in antigenicity loss. Optimal tissue processing is essential. The parameters of optimal storage of unstained slides remain to be defined, as they are directly affected by preanalytic variables. Nevertheless, minimization of exposure to water is required for antigen preservation in FFPE tissue sections.