Developing Genomic Resources and Methods for Studying Long-lived Species

One of our goals is to develop genomic resources that help researchers study long-lived animals. Thus far, our efforts have mostly focused on the naked mole-rat (Heterocephalus glaber). Heterocephalus is capable of living more than 28 years, and is highly resistant to neoplasia making it a unique organism for research on aging and age-related diseases. In 2008 we put forward a proposal to sequence the genome of Heterocephalus. Unfortunately, the proposal was unsuccessful. Therefore, we started a less ambitious project whose goals are to develop genomic resources for Heterocephalus, clone and characterize selected Heterocephalus genes and ultimately create transgenic mice with Heterocephalus genes.

This work is funded by a grant from the Ellison Medical Foundation to George Church at Harvard Medical School who is the PI of this project. Other collaborators include Pedro Magalhães (Liverpool, UK), Shelley Buffenstein (San Antonio, USA), and Chris Faulkes (London).

Project Summary

Naked mole-rats can live over 28 years, significantly longer than similar-sized rodents like mice that do not commonly live more than 4 years. Naked mole-rats also appear to be very resistant to neoplasia. Because of these marked differences in longevity and age-related phenotypes between such similar species, genomic comparisons between them may provide clues about the genetic and molecular basis of species differences in aging. Therefore, the main goal of this project is the identification and characterization of naked mole-rat genes that contributed to the evolution of a long lifespan in this species.

Specifically, this projects aims to: 1) Establish genomic resources for studying naked mole-rats. We will create a library of 100kb bacterial artificial chromosomes and perform end sequencing of BAC clones that will serve as a resource for researchers studying these animals. 2) Clone and sequence candidate genes from naked mole-rats, including genes previously related to aging. We will study whether these genes may have been targets of selection or evolved putative new functional domains in naked mole-rats. 3) Study the functions of selected genes in cell culture using mouse stem cells by replacing the normal mouse gene, either the protein-coding or regulatory sequence, by the naked mole-rat homolog. 4) For the most promising candidates we will create 'knock-in' mice, in which we will assay if cellular alterations observed in vitro are also observed in vivo. Such knock-in mice will be exceptional models to study adaptations of naked mole-rats related to aging and age-related diseases like cancer.