Approaches to studying the genomic architecture of complex birth defects

Abstract

Every year nearly 6 percent of children worldwide are born with a serious congenital malformation, resulting in death or lifelong disability. In the United States, birth defects remain one of the leading causes of infant mortality. Among the common structural congenital defects are conditions known as neural tube defects (NTDs). These are a class of malformation of the brain and spinal cord where the neural tube fails to close during the neurulation. Although NTDs remain among the most pervasive and debilitating of all human developmental anomalies, there is insufficient understanding of their etiology. Previous studies have proposed that complex birth defects like NTDs are likely omnigenic, involving interconnected gene regulatory networks with associated signals throughout the genome. Advances in technologies have allowed researchers to more critically investigate regulatory gene networks in ever increasing detail, informing our understanding of the genetic basis of NTDs. Employing a systematic analysis of these complex birth defects using massively parallel DNA sequencing with stringent bioinformatic algorithms, it is possible to approach a greater level of understanding of the genomic architecture underlying NTDs. Herein, we present a brief overview of different approaches undertaken in our laboratory to dissect out the genetics of susceptibility to NTDs. This involves the use of mouse models to identify candidate genes, as well as large scale whole genome/whole exome (WGS/WES) studies to interrogate the genomic landscape of NTDs. The goal of this research is to elucidate the gene‐environment interactions contributing to NTDs, thus encouraging global research efforts in their prevention.

Embryonic Hypotaurine Levels Contribute to Strain-Dependent Susceptibility in Mouse Models of Valproate-Induced Neural Tube Defects

“…as there is already published evidence to suggest that SWV embryos may metabolize VPA differently. Genomic fine mapping of exencephalic fetuses derived from SWV/C57 backcrossing identified a 33 MB sensitivity locus which contains genes coding for members of the ACSM family of enzymes involved in VPA metabolism ( Taiwo et al, 2020 ). ACSM enzymes catalyze conversion of VPA to valproyl-coA, a critical first step required for further metabolism via mitochondrial β-oxidation.…”

“…Several attempts have been made to discern underlying factors contributing to VPA susceptibility in the SWV strain, which is sometimes referred to as SWV-Fnn. Gene expression analysis revealed strain-dependent alterations in folate and one-carbon metabolism pathway genes ( Finnell et al, 1997 ), and genomic fine mapping has been reported on in several publications over the last 2 decades, where intercrossing the C57 and SWV-Fnn strains led to identification of a candidate sensitivity locus ( Beck, 1999 ; Finnell et al, 2000 ; Beck, 2001 ; Lundberg et al, 2004 ; Taiwo et al, 2020 ). Notably, the sensitivity locus contained all but one member of the acyl-CoA synthetase-medium chain (ACSM) family of genes, the exception being the gene encoding ACSM4.…”

Gene Environment Interactions in the Etiology of Neural Tube Defects

“…We determined that recombination events had occurred in the chromosomal region located between D7Mit285 and D7Mit101 , which cover a 3.3-Mb region. This helped to establish the presence of a chromosomal region that contained a major gene or genes that regulates susceptibility to VPA-induced NTDs in mice ( Figure 1 ; Taiwo et al, 2020 ). More robust genomic tools can now be applied to further refine this region of interest and better define those genetic factors regulating sensitivity to VPA’s teratogenicity in mice.…”

Exploring epigenomic mechanisms of neural tube defects using multi‐omics methods and data

“…7 Their polygenic nature necessitates the use of genomics-based approaches to elucidate the genetic layout underlying them. With the advent of whole-genome sequencing, 8 whole-exome sequencing, 9 and next-generation sequencing (NGS), 10 the cumulative number of genes associated with NTDs has increased. 11 Most of the known candidate genes associated with NTDs are closely associated with the folate metabolic pathway 12 and several developmental signaling processes pivotal for neural tube closure, such as WNT-including the canonical β-catenin/WNT 13 and noncanonical WNT/planar cell polarity (PCP) 14 pathways-and the sonic hedgehog signaling 15 pathways.…”