Faculty
Andrew Lidral Ph.D.
The focus of my research is craniofacial developmental genetics. Specifically, our goal is to identify the genetic causes of craniofacial birth defects, including syndromic and nonsyndromic forms of orofacial clefting which occur in 1/500-1/1000 births. Here in the U.S. most patients are treated in a clinical team setting to coordinate treatment based upon each individual\'s needs. Rehabilitative care, which extends from birth until at least age 18, includes multiple surgeries, procedures and other interventions. More importantly, the social and psychological ramifications from appearing abnormal can have a very adverse effect on the person and their family. Since nonsyndromic clefting is a genetically complex trait, we use a variety of strategies to identify disease genes. Our main focus is to collaborate with other researchers to study nonsyndromic clefting in unique populations whose ethnicity or genetic heritage increase the likelyhood for gene identification. Ongoing collaborations include researchers in Colombia, South America; Pittsburgh, PA and Seattle, WA. Recently we have completed a genome wide scan and have identified a major gene on chromosome 9. We are implementing parallel and complementary strategies to identify the disease gene at this locus. These approaches include linkage and association fine-mapping approaches, sequencing candidate genes and comparative developmental genetics using available mouse models. These mouse models include two strains with cleft lip that we are studying to determine which molecular pathways are affected. Interestingly, these mouse models map to regions that have been positive in our human studies. This is quite exciting because previous studies have shown that providing supplemental folate to these mice reduces the prevalence of clefting. Therefore, the animal studies may translate to prevention strategies in humans.
Jim J Lin Ph.D.
Animal cells exhibit a wide variety of motile activities, which are essential for the formation and function of human tissues. Actin and its binding proteins provide the essential force-generating machinery for these motilities. Our focus is to investigate how actin binding proteins, tropomyosin and caldesmon, work together in regulating actin filament dynamics and function in nonmuscle cells. We have identified human tropomyosin 5 and a colon epithelial protein as potential autoantigen for human ulcerative colitis. In the process of characterizing tropomyosin isoforms in ulcerative colitis, we have cloned a novel tropomyosin isoform, whose gene product is preferentially expressed in precancerous cells. Actin cytoskeleton (tropomyosin 5) also plays an important role in host cell and parasite, Cryptosporidium parvum, interaction during infection. Molecular Mechanisms of Cardiac Development and Function: Using molecular biology approach, we are defining the cis-regulatory elements and trans-activating factors required for the expression of cardiac troponin T gene. Another approach is to isolate and characterize novel stage- and/or region-specific genes during heart development. We have cloned a novel Xin gene, whose gene product is localized at the intercalated discs in cardiac muscle and the myotendinous junctions in skeletal muscle. In the mouse, there are two Xin genes, mXin· and mXin‚. A mXin· knockout mouse line was generated. The mXin·-deficient mouse hearts exhibit cardiac hypertrophy and cardiomyopathy, due to a disruption of intercalated disc and some of sarcomeres. These results showed that mouse Xin· may play a vital role in cardiac development and function. An upregulation of dystrophin protein was observed in our mXin·-null mouse skeletal muscle, whereas a significant increase in mXin· expression was associated with mdx (a mouse model of human Duchenne Muscular Dystrophy) mouse skeletal muscle. This finding suggests a genetics and functional interaction between mXin· and dystrophin proteins. Currently, generation of a mXin‚ knockout mouse line as well as investigation of mXin· role in skeletal muscle are underway.
Ana Llopart Ph.D.
In our laboratory we seek to understand the evolution of the genetic barriers responsible for species being reproductively isolated from one another; ultimately the genetic basis of speciation. Today we know that these barriers often involve genic incompatibilities among alleles that function normally in their usual genetic background and produce perfectly fit genotypes, but generate hybrid dysfunction (i.e. sterility and inviability) when encounter alleles from other species. To gain insight into the evolution of these genetic barriers we study hybrids where incompatibilities become apparent. Our approaches use methodologies that combine classic genetics, modern genomics and population genetics, and an ideal biological system of two very closely related species of fruit flies, Drosophila yakuba and D. santomea, which produce abundant hybrids in nature.
One of our current areas of research is centered on studying the genetic basis of sterility of female hybrids between D. yakuba and D. santomea. Hybrid female sterility is a trait that has been a bit more neglected than that of their counterparts hybrid males. In this system, sterility involves at least one factor of recent evolution in D. yakuba that is placed in the cytoplasm of the hybrid embryo and that is incompatible with D. santomea genes. We are also interested in evaluating natural introgression, that is, the effective exchange of genes between species through rare hybridization in nature. Experiments in the laboratory can be very useful to detect genomic regions associated with isolating barriers, but they seldom capture the full complexity of nature. By identifying genes that are able to transgress species boundaries in the natural habitat we can built introgression landscapes, which allow us to gain valuable insights into the chromosomal location of genes either responsible for local adaptation or involved in hybrid dysfunction. Our third on-going project focuses on a very special type of genic incompatibilities, those between cis-regulatory sequences of genes and transcription factors. Independent evolution of these two interacting components involved in transcription regulation in different species usually leads to breakdown of gene expression in hybrids.
John Logsdon Ph.D.
The Logsdon lab works on a variety of related topics in molecular evolutionary genetics:
SEX & MEIOSIS:
- Exploring the origin and evolution of meiotic genes in diverse eukaryotes.
- Molecular evolution and phylogeny of meiotic genes.
- Isolation of meiosis-related genes from protists and other eukaryotes.
- Functional studies of meiotic genes isolated from diverse eukaryotes.
- Bioinformatic studies of meiosis and recombination/repair genes.
TREES:
- Understanding the molecular phylogeny of eukaryotes.
- Using complex gene families to root the eukaryotic tree of life.
- Isolating new protein genes to address thorny issues in eukaryotic phylogeny.
LATERAL GENE TRANSFER:
- Developing a better understanding of the frequency, roles, distribution and phylogenetic impacts of LGT in prokaryotes.
- Comparative bioinformatics of bacterial genomes.
- Mathematical modeling/ computer simulation.
GENOMES:
- Discovery and analysis of genomic sequence from key protists.
- Comparative bioinformatics of protist genomes as grist for hypothesis-driven research in the lab.
INTRONS:
- Understanding of the origin and evolution of spliceosomal introns
- What are their roles in eukaryotic genome evolution? What is their phylogenetic distribution?
