Dr Richard Badge's projects

1. The impact of L1 retrotransposons on human genetic variation and gene expression

L1 or LINE-1 retrotransposons are autonomous mobile elements ubiquitous in mammalian genomes. L1s constitute around 17% (~461Mb) of the human genome reference sequence, but their contribution to human genome evolution is not only structural. Insertion of L1 and its non-autonomous parasites has caused over 30 cases of human genetic disease. Currently mobile L1 subfamilies are evolutionarily young, and so frequently show presence/absence variation in humans.

Previous studies combining bioinformatics and molecular genomics have revealed very significant inter-individual variation in human L1 complement and suggest that this may contribute to medically-relevant genetic variation, for example in disease susceptibility or drug metabolism. Human genomic sequence databases contain only a fraction of global L1 genetic diversity, and this represents a significant gap in our knowledge.

This deficiency is being directly addressed in our group by the application of high-throughput molecular genomic techniques, including Next Generation Sequencing, so bioinformatic tools underpin this research. The development of better tools and resources is a central focus of our efforts and provides an exciting opportunity for students to work and learn at the interface between two of the most rapidly advancing fields in human genetics, bioinformatics and molecular genomics.

Projects available involve bioinformatic assessment of the effects of L1 retrotransposon insertions on human gene expression and developing informatic resources for the analysis and dissemination of human genomic variation data. Opportunities to test the prediction of these analyses in the lab can also form part of PhD projects.

2. Development of retrotransposon based marker systems for use in chimpanzee conservation genetics

Humans and chimpanzees share 99% of their DNA, having diverged from their common ancestor only 6-8 million years ago. However, their genomes contain cohorts of active retrotransposons that have greatly diversified since this split.

Through our collaboration with Twycross Zoo, we have developed systems to directly identify potentially active L1 retrotransposons that vary between individual chimpanzees. These L1 insertions have two valuable properties – firstly they will enable us to characterise the active L1s that continue to remodel the chimpanzee genome, and secondly they are stable, easily-typed genetic markers that can be employed to identify relationships between individuals.

In captive-bred populations the maintenance of genetic diversity is paramount and so additional markers, with high information content that are easily typed, are of value in the conservation genetics of these endangered species.

PhD projects in this area will involve the identification validation and characterisation of potentially active chimpanzee retrotransposons, as well as their assessment as genetic markers for planned breeding programmes at Twycross and other zoos.

3. IAP retrotransposon activity in mouse cell lines deficient in DNA methylation

Mutations in the central DNA methyltransferase (DNMT) genes responsible for de novo and maintenance DNA methylation (DNMT1, DNMT3a/b) are lethal early in mouse embryogenesis, while mutations in DNMT-associated genes (DNMT2 and DNMT3L) have variable phenotypes, from no apparent effect to sterility. However, all these mutations are viable in mouse ES cell lines, which presents an opportunity to examine their effects in isogenic cell lines. IAP retrotransposons are strongly regulated by DNA methylation and DNMT3b embryonic lethality is associated with high levels of IAP expression.

We have developed molecular genomic systems that can monitor the distribution and methylation status of dozens of IAP retrotransposon insertions simultaneously across the mouse genome. PhD projects in this area would involve examining mutant and wildtype mouse ES cell line DNA for evidence of de novo IAP mobilisation, and its relationship to IAP DNA methylation status and cellular methylation competence.

Contact

Dr Richard Badge
+44 (0)116 252 5042
rmb19@leicester.ac.uk

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