2020 Curt Stern Award address: a more perfect clinical genome-how consanguineous populations contribute to the medical annotation of the human genome.

This article is based on the address given by the author at the 2020 virtual meeting of the American Society of Human Genetics (ASHG) on October 26, 2020. The video of the original address can be found at the ASHG website.

Patient-Reported Outcomes and Experiences with Population Genetic Testing Offered Through a Primary Care Network.

Aims: To explore patient experiences in a large-scale primary care-based, preemptive genetic testing program. Methods: Patients who received genetic results from the initiative were invited to participate in an online survey 3 weeks postresult disclosure. A 6-month follow-up survey was sent to assess changes over time. Results: The initial survey was completed by 1646 patients, with 544 completing the 6-month follow-up survey. The following outcomes were high overall: patient-reported understanding of results (cancer: 87%; cardiac: 86%); perceived utility (75%); positive emotions (relieved: 66.8%; happy: 62.0%); family result sharing (67.6%); and satisfaction (87%), although analysis by demographic factors identified groups who may benefit from additional education and emotional support. Results-related health behaviors and discussions with providers increased over time (screening procedures 6.1% to 14.2% p < 0.001; provider discussion 10.3% to 25.3%, p < 0.001), and were more likely to take place for patients with positive cancer and/or cardiac results (39.8% vs. 7.6%, p < 0.001). Forty-seven percent of patients reported insurance discrimination concerns, and most (79.4%) were not familiar with privacy and nondiscrimination laws. Concerns regarding discrimination and negative emotions decreased between the two survey time points (privacy issues 44.6% to 35.1% p < 0.001; life insurance discrimination concerns 35.5% to 29.6%, p = 0.001; anxiety 8.1% to 3.3%, p < 0.001; and uncertainty 19.8% to 12.8%, p < 0.001). These findings led to the development and integration of additional patient resources to improve program implementation. Conclusion: Our findings highlight patient experiences with and areas of need in a community-based genomic screening pilot initiative using a mixed primary care/genetics provider model to deliver precision medicine.

Lessons Learned from Bugs in Models of Human History.

Simulation plays a central role in population genomics studies. Recent years have seen rapid improvements in software efficiency that make it possible to simulate large genomic regions for many individuals sampled from large numbers of populations. As the complexity of the demographic models we study grows, however, there is an ever-increasing opportunity to introduce bugs in their implementation. Here, we describe two errors made in defining population genetic models using the msprime coalescent simulator that have found their way into the published record. We discuss how these errors have affected downstream analyses and give recommendations for software developers and users to reduce the risk of such errors.

When to think outside the autozygome: Best practices for exome sequencing in "consanguineous" families.

Exome sequencing (ES) is an effective diagnostic tool with a high yield in consanguineous families. However, how diagnostic yield and mode of inheritance relate to family structure has not been well delineated. We reviewed ES results from families enrolled in the Care4Rare Canada research consortium with various degrees of consanguinity. We contrasted the diagnostic yield in families with parents who are second cousins or closer ("close" consanguinity) vs those more distantly related or from isolated populations ("presumed" consanguinity). We further stratified by number of affected individuals (multiple affected ["multiplex"] vs single affected [simplex]). The overall yield in 116 families was 45.7% (n = 53) with no significant difference between subgroups. Homozygous variants accounted for 100% and 75% of diagnoses in close and presumed consanguineous multiplex families, respectively. In simplex presumed consanguineous families, a striking 46.2% of diagnoses were due to de novo variants, vs only 11.8% in simplex closely consanguineous families (88.2% homozygous). Our data underscores the high yield of ES in consanguineous families and highlights that while a singleton approach may frequently be reasonable and a responsible use of resources, trio sequencing should be strongly considered in simplex families in the absence of confirmed consanguinity given the proportion of de novo variants.

Genetic Variation and Response to Neurocritical Illness: a Powerful Approach to Identify Novel Pathophysiological Mechanisms and Therapeutic Targets.

Disease-specific therapeutic options for critically ill neurological patients are limited. The identification of new preventive, therapeutic, and rehabilitation strategies is of the utmost importance in the field of neurocritical care research. Population genetics offers powerful tools to identify and prioritize biological pathways to be targeted by novel interventions. New treatments with supportive genetic evidence have twice the chances of obtaining final FDA approval compared to those without this support. Large collaborations, public access to data, reproducible science, and innovative analytical methods have exponentially increased the pace of discoveries related to neurocritical care genetics.

The importance of fine-scale studies for integrating paleogenomics and archaeology.

There has been an undercurrent of intellectual tension between geneticists studying human population history and archaeologists for almost 40 years. The rapid development of paleogenomics, with geneticists working on the very material discovered by archaeologists, appears to have recently heightened this tension. The relationship between these two fields thus far has largely been of a multidisciplinary nature, with archaeologists providing the raw materials for sequencing, as well as a scaffold of hypotheses based on interpretation of archaeological cultures from which the geneticists can ground their inferences from the genomic data. Much of this work has taken place in the context of western Eurasia, which is acting as testing ground for the interaction between the disciplines. Perhaps the major finding has not been any particular historical episode, but rather the apparent pervasiveness of migration events, some apparently of substantial scale, over the past ∼5000 years, challenging the prevailing view of archaeology that largely dismissed migration as a driving force of cultural change in the 1960s. However, while the genetic evidence for `migration' is generally statistically sound, the description of these events as structured behaviours is lacking, which, coupled with often over simplistic archaeological definitions, prevents the use of this information by archaeologists for studying the social processes they are interested in. In order to integrate paleogenomics and archaeology in a truly interdisciplinary manner, it will be necessary to focus less on grand narratives over space and time, and instead integrate genomic data with other form of archaeological information at the level of individual communities to understand the internal social dynamics, which can then be connected amongst communities to model migration at a regional level. A smattering of recent studies have begun to follow this approach, resulting in inferences that are not only helping ask questions that are currently relevant to archaeologists, but also potentially opening up new avenues of research.

[Progress on Molecular Biology for Forensic Ancestry Inference].

Forensic ancestry inference refers to the application of ancestry inference of population genetics in forensic practice, which aims to assist police investigation and judicial trial. With the rapid development and extensive use of genomics, DNA as a direct carrier of genetic information, has soon replaced various phenotypic markers and become the main research topics of forensic ancestry inference. This paper reviews different kinds of genetic markers used for forensic ancestry inference, the statistical analysis methods applied, and the prospects of the development in this field.

[Genes and longevity: new data, new controversies]. / Gènes et longévité : nouvelles données, nouvelles controverses - Chroniques génomiques.

Analysis of a huge human pedigree constructed using public genealogy databases indicates that the heritability of longevity is probably lower than previously accepted (0.10 to 0.15 instead of 0.25 to 0.30). This makes the search for "longevity genes" even harder than expected; nevertheless, some significant results emerge and may eventually, after confirmation and extension, provide useful insights.

Electronic health records: the next wave of complex disease genetics.

The combination of electronic health records (EHRs) with genetic data has ushered in the next wave of complex disease genetics. Population-based biobanks and other large cohorts provide sufficient sample sizes to identify novel genetic associations across the hundreds to thousands of phenotypes gleaned from EHRs. In this review, we summarize the current state of these EHR-linked biobanks, explore ongoing methods development in the field and highlight recent discoveries of genetic associations. We enumerate the many existing biobanks with EHRs linked to genetic data, many of which are available to researchers via application and contain sample sizes >50 000. We also discuss the computational and statistical considerations for analysis of such large datasets including mixed models, phenotype curation and cloud computing. Finally, we demonstrate how genome-wide association studies and phenome-wide association studies have identified novel genetic findings for complex diseases, specifically cardiometabolic traits. As more researchers employ innovative hypotheses and analysis approaches to study EHR-linked biobanks, we anticipate a richer understanding of the genetic etiology of complex diseases.

The importance of cohort studies in the post-GWAS era.

The past decade has seen enormous success of wide-scale genetic studies in identifying genetic variants that modify individuals' predisposition to common diseases. However, the interpretation and functional understanding of these variants lag far behind. In this Perspective, we discuss opportunities for using large-scale cohort studies to investigate the downstream molecular effects of SNPs at different 'omics' data levels. We point to the pivotal role of population cohorts in establishing causality and advancing drug discovery. In particular, we focus on the breadth-versus-depth concepts of population studies, on data harmonization, and on the challenges, ethical aspects and future perspectives of cohort studies.

Progress on Molecular Biology for Forensic Ancestry Inference / 法医学杂志

Forensic ancestry inference refers to the application of ancestry inference of population genetics in forensic practice, which aims to assist police investigation and judicial trial. With the rapid development and extensive use of genomics, DNA as a direct carrier of genetic information, has soon replaced various phenotypic markers and become the main research topics of forensic ancestry inference. This paper reviews different kinds of genetic markers used for forensic ancestry inference, the statistical analysis methods applied, and the prospects of the development in this field.

Spatial gene drives and pushed genetic waves.

Gene drives have the potential to rapidly replace a harmful wild-type allele with a gene drive allele engineered to have desired functionalities. However, an accidental or premature release of a gene drive construct to the natural environment could damage an ecosystem irreversibly. Thus, it is important to understand the spatiotemporal consequences of the super-Mendelian population genetics before potential applications. Here, we use a reaction-diffusion model for sexually reproducing diploid organisms to study how a locally introduced gene drive allele spreads to replace the wild-type allele, although it possesses a selective disadvantage s > 0. Using methods developed by Barton and collaborators, we show that socially responsible gene drives require 0.5 < s < 0.697, a rather narrow range. In this "pushed wave" regime, the spatial spreading of gene drives will be initiated only when the initial frequency distribution is above a threshold profile called "critical propagule," which acts as a safeguard against accidental release. We also study how the spatial spread of the pushed wave can be stopped by making gene drives uniquely vulnerable ("sensitizing drive") in a way that is harmless for a wild-type allele. Finally, we show that appropriately sensitized drives in two dimensions can be stopped, even by imperfect barriers perforated by a series of gaps.

Resequencing Helminth Genomes for Population and Genetic Studies.

Next-generation sequencing has become increasingly accessible and economical, making genome-wide studies routine for many species, including humans, model organisms, and domestic livestock. However, in the case of helminth parasites, there are still major practical challenges to the application of these approaches for genetic and population studies. Dozens to hundreds of individual parasites from multiple populations may need to be re-sequenced which, together with the relatively large size of helminth genomes, can still make whole-genome resequencing of individual parasites unfeasible for many studies. Fortunately, there are alternative approaches to the complete sequencing of genomes when conducting genome-wide studies. Here we review some strategies, including genome subsampling and pooling, that enable genome-wide analysis of large numbers of parasites in populations.

Population genetics from 1966 to 2016.

We describe the astonishing changes and progress that have occurred in the field of population genetics over the past 50 years, slightly longer than the time since the first Population Genetics Group (PGG) meeting in January 1968. We review the major questions and controversies that have preoccupied population geneticists during this time (and were often hotly debated at PGG meetings). We show how theoretical and empirical work has combined to generate a highly productive interaction involving successive developments in the ability to characterise variability at the molecular level, to apply mathematical models to the interpretation of the data and to use the results to answer biologically important questions, even in nonmodel organisms. We also describe the changes from a field that was largely dominated by UK and North American biologists to a much more international one (with the PGG meetings having made important contributions to the increased number of population geneticists in several European countries). Although we concentrate on the earlier history of the field, because developments in recent years are more familiar to most contemporary researchers, we end with a brief outline of topics in which new understanding is still actively developing.