Journal Of Human Genetics Research Articles

Юрій Дуброва (1955–2023) — біолог з України, якого чув світ: нотатки до біографії

The future famous geneticist Prof. Yuri Dubrova (1955–2023) was born in Kyiv (Ukraine), where he received excellent secondary and higher education and was awarded with a gold medal upon graduating from school. Eventually, he became one of the best graduates of the Department of Vertebrate Zoology at the Faculty of Biology of Taras Shevchenko National University of Kyiv. His interests included theoretical biology, evolutionary theory, genetics, biometrics, and bionics (for some time he studied the lateral lineage of cyprinid fishes). In his last years at the university, he focused on the study of spontaneous mutations. At the Vavilov Institute of General Genetics in Moscow, Y. Dubrova continued his post-graduate studies and successfully defended his PhD thesis. After the collapse of the USSR, he moved to the UK in search of better scientific and technical opportunities, where he became a professor at the University of Leicester. The scientist lived and worked in Leicester until the end of his life. He devoted himself fully to science, especially to radiation, medical and population genetics, and to teaching, and tried to participate in the study of highly complex medical and genetic issues related, in particular, to the consequences of man-made disasters—Chornobyl (Ukraine, Belarus), Semipalatinsk (Kazakhstan)—and other cases of large-scale radiation effects on life. Dr. Dubrova is the author and co-author of more than 150 scientific articles published in leading journals, including the American Journal of Human Genetics, International Journal of Radiation Biology, Radiation Research, Molecular Biology and Evolution, International Journal of Cancer, British Journal of Cancer, Science, and Nature. He co-operated with many of the world’s leading geneticists and gave lectures in Ukraine, Russia, the USA, Canada, Japan, etc. The article uses fragments of the author’s long correspondence with Y. Dubrova, which may be of interest to biographers of F. Dobrzhansky, M. Tymofeiev-Resovsky, O. Sozinov, O. Yablokov, O. Kistiakowsky, as well as to students, teachers, and historians of Kyiv National University, Kaniv Nature Reserve, and the University of Leicester.

From older to younger: intergenerational promotion of health behaviours in Portuguese families affected by familial amyloid polyneuropathy – Plain Language Summary

What is this summary about? This is a plain language summary of an article originally published in European Journal of Human Genetics. Transthyretin amyloidosis (ATTR) is a disease that affects the heart and nerves of those it afflicts. One inherited form of ATTR is particularly common among people of Portuguese descent and presents primarily as a neurologic disease termed familial amyloid polyneuropathy (FAP). What were the results? This study showed the relevance of communication from older to younger generations, primarily women, among Portuguese families with FAP. There were 4 major patterns of communication, which were in general supportive and informative. This study suggests opportunities for healthcare providers to help their patients regarding communications of inherited diseases within their families. What do the results mean? This study showed the benefits of positive intergenerational communications when discussing inherited diseases in families.

Comparison of a STIR- and T1-based radiomics model to differentiate between plexiform neurofibromas and malignant peripheral nerve sheath tumors in neurofibromatosis type 1 (NF1) (S17.010)

Comparison of a STIR- and T1-based radiomics model to differentiate between plexiform neurofibromas and malignant peripheral nerve sheath tumors in neurofibromatosis type 1 (NF1) (S17.010)

Challenges of accurately estimating sex-biased admixture from X chromosomal and autosomal ancestry proportions

Sex-biased admixture can be inferred from ancestry-specific proportions of X chromosome and autosomes. In a paper published in the American Journal of Human Genetics, Micheletti etal.1 used this approach to quantify male and female contributions following the transatlantic slave trade. Using a large dataset from 23andMe, they concluded that African and European contributions to gene pools in the Americas were much more sex biased than previously thought. We show that the reported extreme sex-specific contributions can be attributed to unassigned genetic ancestry as well as the limitations of simple models of sex-biased admixture. Unassigned ancestry proportions in the study by Micheletti etal. ranged from ∼1% to 21%, depending on the type of chromosome and geographic region. A sensitivity analysis illustrates how this unassigned ancestry can create false patterns of sex bias and that mathematical models are highly sensitive to slight sampling errors when inferring mean ancestry proportions, making confidence intervals necessary. Thus, unassigned ancestry and the sensitivity of the models effectively prohibit the interpretation of estimated sex biases for many geographic regions in Micheletti etal. Furthermore, Micheletti etal. assumed models of a single admixture event. Using simulations, we find that violations of demographic assumptions, such as subsequent gene flow and/or sex-specific assortative mating, may have confounded the analyses of Micheletti etal., but unassigned ancestry was likely the more important confounding factor. Our findings underscore the importance of using complete ancestry information, sufficiently large sample sizes, and appropriate models when inferring sex-biased patterns of demography. This Matters Arising paper is in response to Micheletti etal.,1 published in American Journal of Human Genetics. See also the response by Micheletti etal.,2 published in this issue.

Low disease risk and penetrance in Leber hereditary optic neuropathy

The risk of Leber hereditary optic neuropathy (LHON) has largely been extrapolated from disease cohorts, which underestimate the population prevalence of pathogenic primary LHON variants as a result of incomplete disease penetrance. Understanding the true population prevalence of primary LHON variants, alongside the rate of clinical disease, provides a better understanding of disease risk and variant penetrance. We identified pathogenic primary LHON variants in whole-genome sequencing data of a well-characterized population-based control cohort and found that the prevalence is far greater than previously estimated, as it occurs in approximately 1 in 800 individuals. Accordingly, we were able to more accurately estimate population risk and disease penetrance in LHON variant carriers, validating our findings by using other large control datasets. These findings will inform accurate counseling in relation to the risk of vision loss in LHON variant carriers and disease manifestation in their family. This Matters Arising paper is in response to Lopez Sanchez etal. (2021), published in The American Journal of Human Genetics. See also the response by Mackey etal. (2022), published in this issue.

Is the disease risk and penetrance in Leber hereditary optic neuropathy actually low?

Pedigree analysis showed that a large proportion of Leber hereditary optic neuropathy (LHON) family members who carry a mitochondrial risk variant never lose vision. Mitochondrial haplotype appears to be a major factor influencing the risk of vision loss from LHON. Mitochondrial variants, including m.14484T>C and m.11778G>A, have been added to gene arrays, and thus many patients and research participants are tested for LHON mutations. Analysis of the UK Biobank and Australian cohort studies found more than 1 in 1,000 people in the general population carry either the m.14484T>C or the m.11778G>A LHON variant. None of the subset of carriers examined had visual acuity at 20/200 or worse, suggesting a very low penetrance of LHON. Haplogroup analysis of m.14484T>C carriers showed a high rate of haplogroup U subclades, previously shown to have low penetrance in pedigrees. Penetrance calculations of the general population are lower than pedigree calculations, most likely because of modifier genetic factors. This Matters Arising Response paper addresses the Watson etal. (2022) Matters Arising paper, published concurrently in The American Journal of Human Genetics.

The European Journal of Human Genetics is turning 30: a selection of major cancer genetics papers published by the Journal.

The European Journal of Human Genetics is turning 30: a selection of major cancer genetics papers published by the Journal.

Statement on storage and use of genetic materials

Addendum to: “Statement on Storage and Use of Genetic Materials.” John A. Phillips III, MD, Maimon Cohen, MD, Lynn D. Fleisher, PhD, JD, Ann C. M. Smith, MA, and Ellen Wright Clayton, MD, JD; American College of Medical Genetics Storage of Genetics Materials Committee. American Journal of Human Genetics 57:1499-1500; published December 1995.

Response to Wyckelsma et al.: Loss of α-actinin-3 during human evolution provides superior cold resilience and muscle heat generation

The common loss-of-function mutation R577X in the structural muscle protein ACTN3 emerged as a potential target of positive selection from early studies and has been the focus of insightful physiological work suggesting a significant impact on muscle metabolism. Adaptation to cold climates has been proposed as a key adaptive mechanism explaining its global allele frequency patterns. Here, we re-examine this hypothesis analyzing modern (n= 3,626) and ancient (n= 1,651) genomic data by using allele-frequency as well as haplotype homozygosity-based methods. The presented results are more consistent with genetic drift rather than selection in cold climates as the main driver of the ACTN3 R577X frequency distribution in human populations across the world. This Matters Arising paper is in response to Wyckelsma etal. (2021),1 published in The American Journal of Human Genetics. See also the response by Wyckelsma etal. (2022),2 published in this issue.

The First Baby Born After Polygenic Embryo Screening

The First Baby Born After Polygenic Embryo Screening

Honoring Gregor Mendel

This theme issue, devoted to genetics, acknowledges the centrality of that discipline, in conjunction with evolution, to our understanding of the history and nature of life on earth. Gregor Mendel and Charles Darwin, the recognized founders of their deeply intertwined fields, are—or should be—inseparable in biology education.Although Darwin’s work ultimately provided biology with its enduring conceptual basis—evolution by natural selection—he died unable to answer two central questions: Where does the biological variation central to differential selection reside, and how is it transmitted from one generation to the next? As James P. Evans details in his feature article in this issue, Mendel, whose 200th birthday occurs in July of this year, provided those answers, demonstrating the particulate nature of inheritance and the principles of segregation and independent assortment.Unfortunately, Mendel’s work escaped the attention of his contemporaries, including Darwin, attracting notice only with the rediscovery of his now-classic 1865 paper in 1900. The growth of genetics as a central biological discipline followed in short order, and the new field ultimately was joined to evolutionary biology by extensive mathematical formulations in population genetics. The resulting “modern synthesis of evolution” occurred in the 1930s and 1940s and continues to serve, with amendments, as a framework for research in biology and biomedicine. So central is that framework to the life sciences that in 1973 this journal published Theodosius Dobzhansky’s now-famous article declaring that “nothing in biology makes sense except in the light of evolution.” Genetics provides much of the integral supporting structure for evolution theory, including the mechanisms for the variation that is fuel for the fires of selection and for the smooth transmission of information that maintains biological continuity within species.Genetics is the study of inherited biological variation, though in some four decades of my asking diverse audiences—students, teachers, health professionals, the public—to define the subject, the concept of variation has arisen only rarely without prompting. Perhaps that lack of recognition is a function of the way we approach genetics in formal educational settings and in the media broadly defined. In those settings, the focus generally is structures and processes—chromosomes, meiosis, DNA, genes, replication, genomes, sequencing—all while failing to emphasize the underlying messages of the discipline.Recently, as the world has struggled to understand and control COVID-19, the concept of biological variation has come to the fore for the public in inescapable and often worrying updates on the variants of SARS CoV-2. In the September 2020 ABT Guest Commentary, Gordon Uno discussed the opportunities COVID-19 provides to address genetic variation and evolution in the classroom, as we track the evolution of this virus in real time. Uno’s observation is apt, and we have traversed about 120 years from the rediscovery of Mendel’s work on the “factors” carrying variation to the extraordinary ability to elaborate variation at the level of individual DNA bases, where it is encoded in a universal, digital information molecule. The recent literature carries the news that a large team of scientists has filled in the previously intractable gaps in the human genome and in the process has uncovered more than two million new indications of human genetic variation.Advances in sequencing technology also have generated the genomic sequences of many other species, and their individual and collective analyses affirm that, as Darwin demonstrated, all of life shares a single history and is related by descent with modification. The unity of life was long evident from previous work in fields such as comparative anatomy and embryology, but access to complete genetic sequences has made our understanding of the underlying relationships even more certain, in some cases even allowing revisions in systematics and taxonomy.As important as Mendelian genetics is, we have, unfortunately, allowed the venerable priest’s original formulations to become a bit of an impediment in our instruction, which often emphasizes single-gene disorders because they illustrate Mendelian inheritance. That focus ignores the reality that most human traits, including many of the world’s leading causes of morbidity and mortality, result from the interactions of multiple genes with environmental variables. Indeed, a 2009 article by Michael Dougherty in the American Journal of Human Genetics proposed that we begin genetics instruction with examples of complex, quantitative traits, rather than traditional single-gene characters.In any case, genetics encompasses much more than genetic disease, and the diverse articles in this special issue demonstrate the pervasive nature of genetics and the questions its concepts and tools allow scientists to pursue. The amount of genetics knowledge now available challenges us not to get lost in the ever-accumulating details as we teach. Darwin knew that variation is the rule, not the exception, in the living world. Mendel helped us to understand how variation is transmitted. We should constantly remind students that the structures and processes we describe as we teach genetics exist to harbor, preserve, and transmit biological variation, the lifeblood of any species.

2021 at European Journal of Human Genetics: the year in review.

2021 at European Journal of Human Genetics: the year in review.

Estimation of the journal distance of Genomics & Informatics from other bioinformatics-driven journals, 2003-2018.

This study explored the trends of Genomics & Informatics during the period of 2003-2018 in comparison with 11 other scholarly journals: BMC Bioinformatics, Algorithms for Molecular Biology: AMB, BMC Systems Biology, Journal of Computational Biology, Briefings in Bioinformatics, BMC Genomics, Nucleic Acids Research, American Journal of Human Genetics, Oncogenesis, Disease Markers, and Microarrays. In total, 22,423 research articles were reviewed. Content analysis was the main method employed in the current research. The results were interpreted using descriptive analysis, a clustering analysis, word embedding, and deep learning techniques. Trends are discussed for the 12 journals, both individually and collectively. This is an extension of our previous study (PMCID: PMC6808643).

229. A Novel ‘One Health’ Approach to Understanding the Relationship of Antimicrobial Resistance Characteristics Among Humans, Bovines, and Canines

Background‘One Health’ recognizes the interconnectivity of humans with their production and companion animals, and the environment. Emergence and transmission of antimicrobial resistance (AMR) within and between these compartments is a recognized global threat that requires further understanding to design interventions protecting both human and animal health. In this study we identified resistance gene targets and clonotypes of Escherichia coli recovered from human, canine and bovine hosts and applied non-linear dimensionality reduction and visualization techniques to identify genetic relationships that may otherwise be unobservable within the data. MethodsNon-duplicative E. coli isolates (N=3398; see Figure captions) were collected from humans, canines, bovines from the Midwest USA. We identified beta-lactamase gene targets for third-generation cephem multidrug resistant isolates and performed clonotype analysis on each. Uniform Manifold Approximation (UMAP) was used to create a two-dimensional “map” of the high dimensional space of the genetic results to identify similarities between both infecting and colonizing isolates, and between susceptible and resistant isolates in humans and animals in the study region (see Figure captions). ResultsThe resulting “map” highlights similarities in: 1) genetic patterns of AMR among animals and humans, and 2) links between isolates that are infecting and colonizing in humans and canines (Figures 1-2). Our results suggest that there is strong genetic overlap linking human and animal patterns of AMR. UMAP also identified genetic segments that are unique to humans, distinct outliers, and suggest limited exchange among the neighboring counties (Figure 3).Figure 1. Distribution of infection and surveillance isolates shows distinct clusters and distribution within host species in the UMAP space. Each panel of the figure shows the same UMAP space with the labeled species in color and the other points in grey as a reference. The UMAP space is a non-linear two-dimensional representation of the genetic information contained in the clonotype analysis. UMAP is a dimensionality reduction technique similar to principal component analysis (PCA), except that it uses a non-linear combination of the underlying dimensions, which highlights the local structure and grouping of the cases. For more details see: Diaz-Papkovich, A., Anderson-Trocmé, L., & Gravel, S. (2021). A review of UMAP in population genetics. Journal of Human Genetics, 66(1), 85–91. Infection isolates: no bovine isolates tested, canine n=190, human n=115. Surveillance isolates: bovine n=175, canine n=747, human n=2171.Figure 2. Distribution of resistant and susceptible isolates shows the resistant cases are distributed in small clusters surrounding a large cluster of predominantly susceptible cases. This figure plots the same cases on the same UMAP space as Figure 1. The only difference is the color that distinguishes between resistant and susceptible cases. Resistant isolates: bovine n=91, canine n=300; human n=238. Susceptible isolates: bovine n=84. canine=637, human n=2048.Figure 3. The proportion of cases from each cluster in four adjoining counties varies considerably. The dark bars show the proportion of cases falling into each cluster for each county. The light bars provide a reference point for interpreting the dark bars by showing the proportion of cases falling into each cluster across all four counties. When the dark bars exceed the light bars it indicates that the proportion of cases in that cluster exceeds that of the neighboring counties, such as Cluster 2 for Taylor county and Cluster 3 for Marathon county. All counties shown include a population of at least 20,000. These stipulations are in compliance with federal (HIPAA) guidelines.ConclusionThe results support that UMAP is a valuable tool for visualizing genetic AMR links across species. Human-animal transmission is likely for disparate and common clonotypes. Disclosures All Authors: No reported disclosures

Evolving use of ancestry, ethnicity, and race in genetics research—A survey spanning seven decades

SummaryTo inform continuous and rigorous reflection about the description of human populations in genomics research, this study investigates the historical and contemporary use of the terms “ancestry,” “ethnicity,” “race,” and other population labels in The American Journal of Human Genetics from 1949 to 2018. We characterize these terms’ frequency of use and assess their odds of co-occurrence with a set of social and genetic topical terms. Throughout The Journal’s 70-year history, “ancestry” and “ethnicity” have increased in use, appearing in 33% and 26% of articles in 2009–2018, while the use of “race” has decreased, occurring in 4% of articles in 2009–2018. Although its overall use has declined, the odds of “race” appearing in the presence of “ethnicity” has increased relative to the odds of occurring in its absence. Forms of population descriptors “Caucasian” and “Negro” have largely disappeared from The Journal (<1% of articles in 2009–2018). Conversely, the continental labels “African,” “Asian,” and “European” have increased in use and appear in 18%, 14%, and 42% of articles from 2009–2018, respectively. Decreasing uses of the terms “race,” “Caucasian,” and “Negro” are indicative of a transition away from the field’s history of explicitly biological race science; at the same time, the increasing use of “ancestry,” “ethnicity,” and continental labels should serve to motivate ongoing reflection as the terminology used to describe genetic variation continues to evolve.

Genomic medicine year in review: 2021

Genomic medicine year in review: 2021

Recurrent Germline Variant in the Cohesin Complex Gene RAD21 Predisposes Children to Lymphoblastic Leukemia and Lymphoma

Introduction: Cohesin complex genes are commonly mutated in cancer particularly in myeloid malignancies. Yet patients with germline mutations in cohesin genes, leading to cohesinopathies like Cornelia-de-Lange syndrome (CdLS) are generally not known to be tumor-prone. The complex plays a major role in chromosome alignment and segregation (Uhlmann, Nature Reviews Molecular Cell Biology, 2016), homologous recombination-driven DNA repair (Ström et al., Molecular Cell, 2004) and regulation of gene expression (Busslinger et al., Nature, 2017). To deepen the understanding of cohesin variants in cancer predisposition, we performed TRIO Sequencing in two independent pediatric cancer cohorts. Thereby, we identified a novel recurrent heterozygous germline variant in the cohesin gene RAD21 not described in CdLS patients , located in the binding domain of the cofactors WAPL and PDS5B .Methods: Whole exome sequencing (WES) in a TRIO (child-parent datasets) setting was carried out in two independent, unselected cancer cohorts (TRIO-D, n=158 (Wagener et al., European Journal of Human Genetics, 2021) and TRIO-DD, n=60). To investigate the oncogenic potential of the novel RAD21 variant molecular and functional assessment was performed focusing on potential implications on the complex.Results: The newly identified RAD21 variant at amino acid position 298 resulting in a Proline to Serine (p.P298S) and a Proline to Alanine exchange, respectively, (p.P298A) is only rarely mutated in the general population (gnomAD database n=118,479; RAD21 p.P298S MAF <10 -6 and RAD21 p.P298A MAF <10 -5). While both patients did not show any signs of CdLS, they both have a remarkable family history of cancer. Patient 1 (13y) was diagnosed with T-cell acute lymphoblastic leukemia (T-ALL) whose father had died from breast cancer (41y), while patient 2 (2y) presented with precursor B-cell lymphoblastic lymphoma (pB-LBL) whose uncle had died from pediatric cancer of unknown subtype (8y).To assess the influence of RAD21 p.P298S/A on the binding capacity of the complex, RAD21 variants and the wildtype (WT) were cloned and transfected into HEK293T cells, respectively. Immunoprecipitation analysis of RAD21 with the cofactors WAPL and PDS5B showed no differential binding between the WT and the variants, suggesting that RAD21 p.P298S/A does not impact the formation of the complex.Nevertheless, on a transcriptional level 83 genes were significantly differentially expressed in RAD21 p.P298S and p.P298A compared to the wildtype (fc>1.5, adj. p-value <0.05) with enrichment of genes in p53 signaling pathways. We further observed an increased number of γH2AX and 53BP1 co-localized foci compared to the WT (p≤0.01; Student's t-test). In line, following ionizing radiation, primary patients' samples showed increased cell cycle arrest at G2/M cell-cycle stage compared to a healthy control (p.P298S: p=0.0049 [6Gy]; p=0.0026 [10Gy]; p.P298A: p=0.0054 [6Gy]; p=0.0006 [10Gy]; Student's t-test).For cross-validation of the germline variant RAD21 p.P298S/A and its potential role in pediatric lymphoblastic malignancies, we analysed a third cohort of 150 children with relapsed ALL (IntReALL) for RAD21 p.P298S/A. We again identified RAD21 p.P298A in a boy (12y) with B-cell precursor acute lymphoblastic leukemia. To compare our data to a non-pediatric cancer setting, a cohort of 2300 young adults (<51 years) with cancer was mined (MASTER program). Here, one patient carrying RAD21 p.P298A with a solid tumor was identified. Therefore, amongst all cohorts, RAD21 p.P298S/A was found to be enriched in pediatric vs. adult cancers (3/479 vs. 1/2299; Fisher's exact test; p=0.018).Conclusion: Taken together, we present for the first time the potential role of RAD21 germline variants in pediatric lymphoblastic malignancies. This may shed new light on the many roles of the cohesin complex and its implication outside the typical syndromal presentation. DisclosuresNo relevant conflicts of interest to declare.

Preconception risk assessment for thalassaemia, sickle cell disease, cystic fibrosis and Tay-Sachs disease.

Globally, about 6% of children are born with a serious birth defect of genetic or partially genetic origin. Carrier screening or testing is one way to identify couples at increased risk of having a child with an autosomal recessive condition. The most common autosomal recessive conditions are thalassaemia, sickle cell disease, cystic fibrosis and Tay-Sachs disease, with higher carrier rates in high-risk populations of specific ancestral backgrounds. Identifying and counselling couples at genetic risk of the conditions before pregnancy enables them to make fully informed reproductive decisions, with some of these choices not being available if testing is only offered in an antenatal setting. This is an update of a previously published review. To assess the effectiveness of systematic preconception genetic risk assessment to enable autonomous reproductive choice and to improve reproductive outcomes in women and their partners who are both identified as carriers of thalassaemia, sickle cell disease, cystic fibrosis and Tay-Sachs disease in healthcare settings when compared to usual care. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Registers. Date of latest search of the registers: 04 August 2021. In addition, we searched for all relevant trials from 1970 (or the date at which the database was first available if after 1970) to date using electronic databases (MEDLINE, Embase, CINAHL, PsycINFO), clinical trial databases (National Institutes of Health, Clinical Trials Search portal of the World Health Organization, metaRegister of controlled clinical trials), and hand searching of key journals and conference abstract books from 1998 to date (European Journal of Human Genetics, Genetics in Medicine, Journal of Community Genetics). We also searched the reference lists of relevant articles, reviews and guidelines and also contacted subject experts in the field to request any unpublished or other published trials. Date of latest search of all these sources: 25 June 2021. SELECTION CRITERIA: Any randomised controlled trials (RCTs) or quasi-RCTs (published or unpublished) comparing reproductive outcomes of systematic preconception genetic risk assessment for thalassaemia, sickle cell disease, cystic fibrosis and Tay-Sachs disease when compared to usual care. We identified 37 papers, describing 22 unique trials which were potentially eligible for inclusion in the review. However, after assessment, we found no RCTs of preconception genetic risk assessment for thalassaemia, sickle cell disease, cystic fibrosis and Tay-Sachs disease. No RCTs of preconception genetic risk assessment for thalassaemia, sickle cell disease, cystic fibrosis and Tay-Sachs disease are included. A trial identified earlier has published its results and has subsequently beenlisted as excluded in this review. As there are no RCTs of preconception genetic risk assessment for thalassaemia, sickle cell disease, cystic fibrosis, or Tay-Sachs disease included in either the earlier or current versions of this review, we recommend considering potential non-RCTs studies (for example prospective cohorts or before-and-after studies) for future reviews. While RCTs are desirable to inform evidence-based practice and robust recommendations, the ethical, legal and social implications associated with using this trial design to evaluate the implementation of preconception genetic risk assessment involving carrier testing and reproductive autonomy must also be considered. In addition, rather than focusing on single gene-by-gene carrier testing for specific autosomal-recessive conditions as the intervention being evaluated, preconception expanded genetic screening should also be included in future searches as this has received much attention in recent years as a more pragmatic strategy. The research evidence for current international policy recommendations is limited to non-randomised studies.

The quantity of health-related article publications from universities in Saudi Arabia: A bibliometric analysis, 2008-2017.

Several studies have summarized the biomedical publications in Arab countries. However, the quantity of health-related article publications from universities in recent years in Saudi Arabia is unknown. Therefore, this study aimed to perform a bibliometric analysis that showcases the quantitative health-related article publications output from universities in Saudi Arabia between 2008 and 2017. An extensive literature search was conducted using the PubMed database. The search was limited to original research articles, systematic reviews, and meta-analyses published in the English language reporting on humans from medicine and health sciences colleges by researchers affiliated with any university in Saudi Arabia between January 2008 and December 2017. A total of 3172 articles were found published between January 2008 and December 2017. The number of publication output increased significantly (p = 0.0027) from 73 (2.3%) in 2008 to 721 (22.7%) in 2017. The highest quantity of publications came from the Riyadh region (n = 2257), specifically King Saud University (n = 1538). Of specific journals, the BioMed Central journals published the most articles by Saudi Arabian researchers (n = 112). The total number of publications increased from 2% to 24.8% by region. However, approximately 80% of the papers were published in journals with an impact factor (IF) <3. Around 3.8% of the papers were published in journals that had an IF ≥6 and has increased significantly (p = 0.030) from 0% to 1.2% in the past decade. The journal with the highest IF that published a high quantity of articles was the American Journal of Human Genetics. This study has identified a continuous significant increase in the publication of health-related articles from universities in Saudi Arabia. This study extended our knowledge of the quantity of scientific productivity in the field of medicine and health sciences over a recent decade.

So many Nigerians: why is Nigeria overrepresented as the ancestral genetic homeland of Legacy African North Americans?

The genetics of African North Americans are complex amalgamations of various West and Central African peoples with modest gene flow from specific European and Amerindian peoples. A comprehensive understanding of African North American biohistory is a prerequisite for accurate interpretations of the ancestral genetics of this population. Too often, genetic interpretations falter with ahistorical reconstructions. The recently reported overrepresentation of Nigerian lineages in African North Americans reflects pronounced limitations in the African genomic database, the artificiality of the colonial maps of Africa, the contributions of multiple African empires and kingdoms into the transatlantic trade in enslaved Africans, and the overrepresentation of Yoruba peoples in the existing limited representation of West Africans in public genomic databases. This Matters Arising paper is in response to Micheletti etal. (2020), published in The American Journal of Human Genetics. See also the response by Micheletti etal. (2020), published in this issue.