Copy Number Variation in Human Disease
The research in Dr. Shaikh’s laboratory focuses on genetic diseases that arise from genomic rearrangements such as microdeletions, microduplications and translocations. These rearrangements may disrupt the integrity of a single gene or result in the altered copy number of several genes. Diseases arising from such structural rearrangements have been designated “genomic disorders” which can manifest phenotypically as multiple congenital anomalies (MCA), including global developmental delay, intellectual disabilities and deficits, cardiac defects and cranio-facial differences. Over the past several years, Dr. Shaikh has collected a large cohort of pediatric subjects with developmental delays and associated phenotypes. They have assessed these subjects for copy number variations (CNVs) using high resolution microarrays with the goal of identifying pathogenic CNVs that underlie the subjects phenotype. The detection of increasingly smaller CNVs and determination of their role in disease continues to be a challenging problem. In order to do this they have developed computational algorithms and databases for improved analysis of copy number data and assessment of the pathological significance of observed CNVs. Dr. Shaikh’s group is developing higher resolution, custom-designed microarrays and next-generation sequencing approaches for CNV detection and a combination of computational and functional genomics approaches to assess their impact on the subject’s phenotype.
Neurodevelopmental Genes and Genetics Pathways
Based on the discovery of pathogenic CNVs in their cohort, Dr. Shaikh and his colleagues are now focusing their efforts on the characterization of the genes that are copy number variant in the affected subjects. Since a majority of the disorders seen in their cohort have a neurological component, they expect to identify genes critical in neurodevelopmental pathways. Using computational tools and available genomic data resources, they have identified candidate genes in many of the newly discovered genomic disorders. These candidate genes were identified based on their known or predicted functions, tissue of expression, available animal models and/or potential role in early development in general and neural development in particular. They are now beginning to analyze the effect of haploinsufficiency of these genes using functional genomics approaches and animal models. Dr. Shaikh’s group is also continuing their work in the area of neuropsychiatric genetics with interests in ADHD, autism spectrum disorders and schizophrenia. They hope to identify genes and genetic pathways that are important in normal brain development based on their analysis of patient cohorts with neurological and neuropsychiatric disorders.
Genome Instabilty and Mechanisms of Rearrangement
Another long standing interest in Dr. Shaikh’s laboratory is the elucidation of the mechanisms underlying the rearrangements that lead to genomic disorders. In several recurrent disorders, the rearrangements are often caused by aberrant recombination occurring at segmental duplications (SDs). SDs are a class of repetitive DNA elements in the human genome ranging in size from 10-500 kb and sharing >90% (typically 96-98%) sequence identity with each other. These regions of genomic instability make up ~5% of the human genome and are expected to be major contributors to the burden of cytogenetic and sub-microscopic chromosomal abnormalities in individuals with developmental disorders. Current data suggests that ~20% of the observed pathogenic CNVs seen in their cohort, result from SD-mediated rearrangements. SDs have had a major impact on the evolution of the primate genome and continue to play a role in human disease and variation. Their continuing work characterizing SDs and other unstable sequences found at rearrangement breakpoints are providing valuable insights into the role of sequence motifs in genome instability.