Shattering the Genome


Image – SPO11 protein purified from mouse spermatocytes with different gene mutations.

Background – Cells that are destined to become sperm and egg make a protein called SPO11, whose purpose is to shatter the genome. The cells then use the ends of each DNA shard to stitch the genome back together. This molecular break-and-repair process is called recombination.

Goal – To understand recombination in mice by catching SPO11 in the act.

Importance – Damaging the genome is dangerous, so recombination is highly scripted. When the script goes off, the sperm or egg cell carries a mutation that can cause a miscarriage or genetic disease.

Why mice? – Mice are a remarkably good model organism for learning how this molecular process works in the human body.

Major findings – The most significant results of this work:

  • showed that a protein called ATM controls the amount of shattering: take ATM away and SPO11 goes wild
  • created a high-resolution map of break propensity in the genome

Significant publications – Lange et al. Nature 2011; Lange et al. Cell 2016 [complete list here]

The Y Chromosome


Image – Microscopy shows an aberrant Y chromosome in a female.

Background – The male-specific chromosome contains massive palindromic sequences. Palindromes – and the genes that reside there – are maintained by a modified version of the recombination process described above.

Goal – To characterize the danger of recombination in Y-chromosome palindromes.

Importance – When recombination in the human Y chromosome goes awry, the sperm cell carries an abnormal Y chromosome that can cause male infertility or sex reversal in offspring.

Samples – DNA isolated from 2,380 patients and cell lines derived from a subset of patients.

Major findings – The most significant results of this work:

  • developed a web-based database of genetic markers for testing the human Y chromosome
  • identified an Achilles' heel in the recombination process that leads to infertility and other sex disorders

Significant publications – Lange et al. Nucleic Acids Research 2008 and website; Lange et al. Cell 2009 [complete list here]

News coverage – This work was covered by an article in The New York Times.

Pediatric Cancer


Image – Rhabdoid tumor cells stained with a dye. Credit AFIP

Background – Rhabdoid tumors are aggressive pediatric cancers of the brain and kidney.

Goal – To identify a gene on chromosome 22 frequently mutated in rhabdoid tumors.

Importance – The genetic signatures of cancer subtypes inform prognoses and guide treatments.

Approach – Comparison of rhabdoid tumor DNA from 13 patients to find the genetic difference that was common to the tumors.

Major findings – The most significant results of this work:

  • identified a novel tumor suppressor gene

Significant publication – Versteege et al. Nature 1998 [complete list here]