Biomedical subjects

Neil A Hanchard

Publications and source records attributed to Neil A Hanchard.

5 recordsLinked to original sources

PubMed2026

Long-read Sequences Mapped to a Complete Reference Genome Uncover Uncaptured Structural Variants across the Beta-globin Cluster in Africans with Sickle Cell Disease.

African genomes are marked by extensive complexity in the number and distribution of variants, yet remain under-represented in genetic databases and the human reference genome. This gap in representation limits the broad application of genomic medicine. Sickle cell disease (SCD) - one of the most common monogenic diseases - has its highest prevalence in Africa, and variation in disease severity has consistently been linked to the beta-globin locus, including levels of fetal hemoglobin (HbF). Modulation of HbF is central to current SCD gene therapies; however, the inherent complexity and variation at the locus in African genomes presents a challenge to translating these advances to Africa. Here, we align long-read single molecule sequences (LRS) targeted to the beta-globin region to the hg38 and T2T-CHM13v2 genome references in 40 individuals with SCD, predominantly recruited from three African countries. We demonstrate that the expanded T2T-CHM13v2 reference sequence at this locus reduces Structural Variant (SV) calls by 70% and uncovers uncaptured single nucleotide variants (SNVs). Across the cluster we report 343 SVs and 196 SNVs that have not been previously reported, including in LRS data from the All of Us project. By including African populations from ethnolinguistic groups that have not been previously surveyed we improve variant resolution and bolster evidence for observed variation. Finally, we identify a common ∼4kb insertion locus overlapping the HBB promoter among individuals with high HbF. These results demonstrate the utility of combining a comprehensive reference genome with LRS in African populations to uncover genomic variation at disease-associated loci.

SNV↗

PubMed2022

Genetics for all: Tri-directional research engagement as an equitable framework for international partnerships.

Over the past 5 years, human genetics and genomics research has placed a greater emphasis on increasing diversity among research participants and study researchers as a means of expanding the reach of human genetics and the knowledge accrued by it. Within this context, international collaborations between investigators in well-resourced research-funded countries (RFCs) and those in research-underfunded countries (RUCs) have flourished, with the goal of recruiting more geographically diverse participant pools. Past harms to communities engaged in genetics research have underscored the importance of bi-directional relational engagements, in which researchers and communities work together to ensure ethical research practices and participant involvement. Successful collaborations in the global genomics space, however, are often dependent upon RUC stakeholder investigators and physicians, whose needs are frequently either excluded from existing models of bi-directional community engagement or conflated with that of the study community. Here, we advocate for building more equitable international partnerships through the empowerment of RUC stakeholder investigators-a tri-directional engagement model-that includes supporting, building, and validating the efforts of RUC investigators through training, access, and authorship. We highlight existing initiatives that serve as exemplars in this effort and offer a framework for the broader genetics community to support equitable models of international research partnerships while being mindful of practical challenges. The core concepts embodied augment ongoing efforts to diversify the field of human genetics and complement the long-term goal of genetics for all.

Journal Article↗

PubMed2005

Screening for recently selected alleles by analysis of human haplotype similarity.

There is growing interest in the use of haplotype-based methods for detecting recent selection. Here, we describe a method that uses a sliding window to estimate similarity among the haplotypes associated with any given single-nucleotide polymorphism (SNP) allele. We used simulations of natural selection to provide estimates of the empirical power of the method to detect recently selected alleles and found it to be comparable in power to the popular long-range haplotype test and more powerful than methods based on nucleotide diversity. We then applied the method to a recently selected allele--the sickle mutation at the HBB locus--and found it to have a signal of selection that was significantly stronger than that of simulated models both with and without strong selection. Using this method, we also evaluated >4,000 SNPs on chromosome 20, indicating the applicability of the method to regional data sets.

Alleles↗

PubMed2005

Genetic susceptibility and single-nucleotide polymorphisms.

The completion of the Human Genome Project has provided insight into human genetic variation, most commonly represented by single-nucleotide polymorphisms. There is presently a great deal of interest in linking genetic and phenotypic variation in the form of severity of, and susceptibility to, common multifactorial diseases. This article provides a background to recent advances in genetics, focusing on the application to common neonatal disorders and the practical difficulties of genetic association studies, as well as highlighting the potential impact on clinical practice.

Genetic Predisposition to Disease↗

PubMed2003

Evidence for extensive transmission distortion in the human genome.

It is a basic principle of genetics that each chromosome is transmitted from parent to offspring with a probability that is given by Mendel's laws. However, several known biological processes lead to skewed transmission probabilities among surviving offspring and, therefore, to excess genetic sharing among relatives. Examples include in utero selection against deleterious mutations, meiotic drive, and maternal-fetal incompatibility. Although these processes affect our basic understanding of inheritance, little is known about their overall impact in humans or other mammals. In this study, we examined genome screen data from 148 nuclear families, collected without reference to phenotype, to look for departures from Mendelian transmission proportions. Using single-point and multipoint linkage analysis, we detected a modest but significant genomewide shift towards excess genetic sharing among siblings (average sharing of 50.43% for the autosomes; P=.009). Our calculations indicate that many loci with skewed transmission are required to produce a genomewide shift of this magnitude. Since transmission distortion loci are subject to strong selection, this raises interesting questions about the evolutionary forces that keep them polymorphic. Finally, our results also have implications for mapping disease genes and for the genetics of fertility.

Chromosome Mapping↗