The discovery of acatalasemia (lack of catalase in the blood) and its significance in human genetics.

Catalase, a heme-containing antioxidant enzyme, was once considered essential for human survival. It is widely distributed in the human body and is particularly abundant in red blood cells. The term "acatalasemia" first appeared in the Proceedings of the Japan Academy in 1951, drawing global attention to families genetically deficient in catalase. This deficiency not only altered the significance of catalase but also played a pioneering role in human genetics during an era of limited genetic methodology. In this article, we examine the discovery of acatalasemia by an otolaryngologist during surgery on an 11-year-old girl. This remarkable journey led to epoch-making research spanning biochemistry, hematology, and human genetics.

Challenging Misconceptions about Race in Undergraduate Genetics.

Racial biases, which harm marginalized and excluded communities, may be combatted by clarifying misconceptions about race during biology lessons. We developed a human genetics laboratory activity that challenges the misconception that race is biological (biological essentialism). We assessed the relationship between this activity and student outcomes using a survey of students' attitudes about biological essentialism and color-evasive ideology and a concept inventory about phylogeny and human diversity. Students in the human genetics laboratory activity showed a significant decrease in their acceptance of biological essentialism compared with a control group, but did not show changes in color-evasive ideology. Students in both groups exhibited increased knowledge in both areas of the concept inventory, but the gains were larger in the human genetics laboratory. In the second iteration of this activity, we found that only white students' decreases in biological essentialist beliefs were significant and the activity failed to decrease color-evasive ideologies for all students. Concept inventory gains were similar and significant for both white and non-white students in this iteration. Our findings underscore the effectiveness of addressing misconceptions about the biological origins of race and encourage more research on ways to effectively change damaging student attitudes about race in undergraduate genetics education.

Eugenics and the misuse of Mendel.

Highlighting the Distinguished Speakers Symposium on "The Future of Human Genetics and Genomics," this collection of articles is based on presentations at the ASHG 2023 Annual Meeting in Washington, DC, in celebration of all our field has accomplished in the past 75 years, since the founding of ASHG in 1948.

From complete genomes to pangenomes.

Highlighting the Distinguished Speakers Symposium on "The Future of Human Genetics and Genomics," this collection of articles is based on presentations at the ASHG 2023 Annual Meeting in Washington, DC, in celebration of all our field has accomplished in the past 75 years, since the founding of ASHG in 1948.

Gliwice Scientific Meetings as a forum for discussion of research projects.Personal impressions.

The article has been written for the occasion of 25 Anniversary of Gliwice Scientific Meetings (GSN). For this reason, I am going to present scientific contacts of the Institute of Oncology at Gliwice with the Institute of Human Genetics of the Polish Academy of Sciences at Poznan not only at conference occasions but also in regular research manner.

Genetic factors associated with reasons for clinical trial stoppage.

Many drug discovery projects are started but few progress fully through clinical trials to approval. Previous work has shown that human genetics support for the therapeutic hypothesis increases the chance of trial progression. Here, we applied natural language processing to classify the free-text reasons for 28,561 clinical trials that stopped before their endpoints were met. We then evaluated these classes in light of the underlying evidence for the therapeutic hypothesis and target properties. We found that trials are more likely to stop because of a lack of efficacy in the absence of strong genetic evidence from human populations or genetically modified animal models. Furthermore, certain trials are more likely to stop for safety reasons if the drug target gene is highly constrained in human populations and if the gene is broadly expressed across tissues. These results support the growing use of human genetics to evaluate targets for drug discovery programs.

Application of Genomic Medicine in Africa: 14th Conference of the African Society of Human Genetics and the 2nd International Congress of the Moroccan Society of Genomics and Human Genetics, Rabat, Morocco 2022.

The 14th African Society of Human Genetics (AfSHG) Morocco Meeting and 2nd International Congress of the Moroccan Society of Genomics and Human Genetics (SM2GH), held in Rabat, Morocco, from December 12 through 17, 2022, brought together 298 attendees from 23 countries, organized by the AfSHG in collaboration with the SM2GH. The conference's overarching theme was "Applications of Genomics Medicine in Africa," covering a wide range of topics, including population genetics, genetics of infectious diseases, hereditary disorders, cancer genetics, and translational genetics. The conference aimed to address the lag in the field of genetics in Africa and highlight the potential for genetic research and personalized medicine on the continent. The goal was to improve the health of African populations and global communities while nurturing the careers of young African scientists in the field. Distinguished scientists from around the world shared their recent findings in genetics, immunogenetics, genomics, genome editing, immunotherapy, and ethics genomics. Precongress activities included a 2-day bioinformatics workshop, "NGS Analysis for Monogenic Disease in African Populations," and a Young Investigators Forum, providing opportunities for young African researchers to showcase their work. The vast genetic diversity of the African continent poses a significant challenge in investigating and characterizing public health issues at the genetic and functional levels. Training, research, and the development of expertise in genetics, immunology, genomics, and bioinformatics are vital for addressing these challenges and advancing genetics in Africa. The AfSHG is committed to leading efforts to enhance genetic research, coordinate training, and foster research collaborations on the continent.

Integrating Large-Scale Protein Structure Prediction into Human Genetics Research.

The last five years have seen impressive progress in deep learning models applied to protein research. Most notably, sequence-based structure predictions have seen transformative gains in the form of AlphaFold2 and related approaches. Millions of missense protein variants in the human population lack annotations, and these computational methods are a valuable means to prioritize variants for further analysis. Here, we review the recent progress in deep learning models applied to the prediction of protein structure and protein variants, with particular emphasis on their implications for human genetics and health. Improved prediction of protein structures facilitates annotations of the impact of variants on protein stability, protein-protein interaction interfaces, and small-molecule binding pockets. Moreover, it contributes to the study of host-pathogen interactions and the characterization of protein function. As genome sequencing in large cohorts becomes increasingly prevalent, we believe that better integration of state-of-the-art protein informatics technologies into human genetics research is of paramount importance.

Human Genetics and Genomics for Drug Target Identification and Prioritization: Open Targets' Perspective.

Open Targets, a consortium among academic and industry partners, focuses on using human genetics and genomics to provide insights to key questions that build therapeutic hypotheses. Large-scale experiments generate foundational data, and open-source informatic platforms systematically integrate evidence for target-disease relationships and provide dynamic tooling for target prioritization. A locus-to-gene machine learning model uses evidence from genome-wide association studies (GWAS Catalog, UK BioBank, and FinnGen), functional genomic studies, epigenetic studies, and variant effect prediction to predict potential drug targets for complex diseases. These predictions are combined with genetic evidence from gene burden analyses, rare disease genetics, somatic mutations, perturbation assays, pathway analyses, scientific literature, differential expression, and mouse models to systematically build target-disease associations (https://platform.opentargets.org). Scored target attributes such as clinical precedence, tractability, and safety guide target prioritization. Here we provide our perspective on the value and impact of human genetics and genomics for generating therapeutic hypotheses.

Human genetic associations of the airway microbiome in chronic obstructive pulmonary disease.

Little is known about the relationships between human genetics and the airway microbiome. Deeply sequenced airway metagenomics, by simultaneously characterizing the microbiome and host genetics, provide a unique opportunity to assess the microbiome-host genetic associations. Here we performed a co-profiling of microbiome and host genetics with the identification of over 5 million single nucleotide polymorphisms (SNPs) through deep metagenomic sequencing in sputum of 99 chronic obstructive pulmonary disease (COPD) and 36 healthy individuals. Host genetic variation was the most significant factor associated with the microbiome except for geography and disease status, with its top 5 principal components accounting for 12.11% of the microbiome variability. Within COPD individuals, 113 SNPs mapped to candidate genes reported as genetically associated with COPD exhibited associations with 29 microbial species and 48 functional modules (P < 1 × 10-5), where Streptococcus salivarius exhibits the strongest association to SNP rs6917641 in TBC1D32 (P = 9.54 × 10-8). Integration of concurrent host transcriptomic data identified correlations between the expression of host genes and their genetically-linked microbiome features, including NUDT1, MAD1L1 and Veillonella parvula, TTLL9 and Stenotrophomonas maltophilia, and LTA4H and Haemophilus influenzae. Mendelian randomization analyses revealed a potential causal link between PARK7 expression and microbial type III secretion system, and a genetically-mediated association between COPD and increased relative abundance of airway Streptococcus intermedius. These results suggest a previously underappreciated role of host genetics in shaping the airway microbiome and provide fresh hypotheses for genetic-based host-microbiome interactions in COPD.

Human Genetics Society of Australasia Position Statement: Predictive and Presymptomatic Genetic Testing in Adults and Children.

This Position Statement provides guidelines for health professionals who work with individuals and families seeking predictive genetic testing and laboratory staff conducting the tests. It presents the major practical, psychosocial and ethical considerations associated with presymptomatic and predictive genetic testing in adults who have the capacity to make a decision, children and young people who lack capacity, and adults living with reduced or fluctuating cognitive capacity.Predictive Testing Recommendations: (1) Predictive testing in adults, young people and children should only be offered with pretest genetic counseling, and the option of post-test genetic counseling. (2) An individual considering whether to have a predictive test should be supported to make an autonomous and informed decision. Regarding Children and Young People: (1) Predictive testing should only be offered to children and young people for conditions where there is likely to be a direct medical benefit to them through surveillance, use of prevention strategies, or other medical interventions in the immediate future. (2) Where symptoms are likely to develop in childhood, in the absence of direct medical benefit from this knowledge, genetic health professionals and parents/guardians should discuss whether undertaking predictive testing is the best course of action for the child and the family as a whole. (3) Where symptoms are likely to develop in adulthood, the default position should be to postpone predictive testing until the young person achieves the capacity to make an autonomous and informed decision. This is applicable regardless of whether there is some action that can be taken in adulthood.

Genetic and molecular architecture of complex traits.

Human genetics has emerged as one of the most dynamic areas of biology, with a broadening societal impact. In this review, we discuss recent achievements, ongoing efforts, and future challenges in the field. Advances in technology, statistical methods, and the growing scale of research efforts have all provided many insights into the processes that have given rise to the current patterns of genetic variation. Vast maps of genetic associations with human traits and diseases have allowed characterization of their genetic architecture. Finally, studies of molecular and cellular effects of genetic variants have provided insights into biological processes underlying disease. Many outstanding questions remain, but the field is well poised for groundbreaking discoveries as it increases the use of genetic data to understand both the history of our species and its applications to improve human health.

Statements by scientific organizations can, and should, shape society.

Statements based on the best current scientific data and analyses that bear directly on societal issues, especially ones that are critical to societal justice, equity, and health, are practical responsibilities of professional scientific organizations. And they often have impact.

Genome-wide association study identifies human genetic variants associated with fatal outcome from Lassa fever.

Infection with Lassa virus (LASV) can cause Lassa fever, a haemorrhagic illness with an estimated fatality rate of 29.7%, but causes no or mild symptoms in many individuals. Here, to investigate whether human genetic variation underlies the heterogeneity of LASV infection, we carried out genome-wide association studies (GWAS) as well as seroprevalence surveys, human leukocyte antigen typing and high-throughput variant functional characterization assays. We analysed Lassa fever susceptibility and fatal outcomes in 533 cases of Lassa fever and 1,986 population controls recruited over a 7 year period in Nigeria and Sierra Leone. We detected genome-wide significant variant associations with Lassa fever fatal outcomes near GRM7 and LIF in the Nigerian cohort. We also show that a haplotype bearing signatures of positive selection and overlapping LARGE1, a required LASV entry factor, is associated with decreased risk of Lassa fever in the Nigerian cohort but not in the Sierra Leone cohort. Overall, we identified variants and genes that may impact the risk of severe Lassa fever, demonstrating how GWAS can provide insight into viral pathogenesis.

Personal journeys to and in human genetics and dysmorphology.

Genetics has become a critical component of medicine over the past five to six decades. Alongside genetics, a relatively new discipline, dysmorphology, has also begun to play an important role in providing critically important diagnoses to individuals and families. Both have become indispensable to unraveling rare diseases. Almost every medical specialty relies on individuals experienced in these specialties to provide diagnoses for patients who present themselves to other doctors. Additionally, both specialties have become reliant on molecular geneticists to identify genes associated with human disorders. Many of the medical geneticists, dysmorphologists, and molecular geneticists traveled a circuitous route before arriving at the position they occupied. The purpose of collecting the memoirs contained in this article was to convey to the reader that many of the individuals who contributed to the advancement of genetics and dysmorphology since the late 1960s/early 1970s traveled along a journey based on many chances taken, replying to the necessities they faced along the way before finding full enjoyment in the practice of medical and human genetics or dysmorphology. Additionally, and of equal importance, all exhibited an ability to evolve with their field of expertise as human genetics became human genomics with the development of novel technologies.