telomeres are double trouble

1
Mapping QTLs in the mouse is important for determining the genetic basis of complex traits in mice and humans, and mapping QTLs to a high-enough resolu- tion to select candidate genes requires fine-scale maps. Now, Sagiv Shifman, Jonathan Flint and colleagues have produced a genetic map of the mouse genome using more than 10,000 SNP markers, making this the highest-resolution genetic map for any organism except humans. As well as being a useful mapping tool, this map provides a detailed picture of patterns of recombina- tion across the mouse genome. In fact, the authors have pro- duced several SNP maps — one using an outbred population of 2,300 mice (resulting in separate maps for males and females), and another using eight sets of recombinant inbred lines (a total of 273 lines). Genetic maps describe the relative positions of markers across the genome according to how often recombi- nation events occur between them. By comparing their SNP maps with a physical map of the mouse genome (the genome sequence itself), the authors pro- duced a picture of the density of recombination events across the genome. In humans, recombination is known to evolve rapidly on a small scale (there is little correlation between the positions of recom- bination hotspots in human and chimpanzees), but recombination patterns on a larger scale seem to be more constrained. The authors examined the regions of recombi- nation ‘deserts’ (in which there is low recombination) and ‘jungles’ (regions of high recombination, including recombination hotspots). They show that several factors that are known to predict recombina- tion rates in human genomes also predict recombination MOUSE GENOMICS Crossing the map In the 1930s, Dobzhansky and Muller — two pioneers of fly genetics — proposed that hybrid incompatibilties that contribute to speciation are caused by interactions between genes that have functionally diverged between the hybridizing species. Seventy years later, Daniel Barbash and colleagues have identified the first such pair of genes that cause male lethality in crosses between two Drosophila species. One of the partners encodes a protein that localizes to a heterochromatic region, and the authors suggest that the rapid evolution of sequences in this region has driven the evolution of the incompatibility gene. Several genes that contribute to speciation are known, but none fulfils the three Dobzhansky–Muller criteria: reduced fitness of the hybrid; functional divergence between the two hybridizing species; and dependence of a pair of genes on each other to cause their incompatibility effects. No male flies are produced in crosses between Drosophila melanogaster females and Drosophila simulans males. It was previously shown that the Lhr 1 mutation in D. simulans and a mutation in Hmr in D. melanogaster suppress this lethality, and genetic interaction studies hinted that there was something ‘Dobzhansky– Mullerian’ about this behaviour. Hmr is known to be X-linked and to encode a rapidly evolving DNA-binding protein with an MADF domain. The authors used a combination of mapping and candidate-gene approaches to clone the Lhr gene EVOLUTION The first Dobzhansky–Muller pair …not only are recombination patterns well conserved on a large scale, they are influenced by similar chromosomal and sequence characteristics across mammals. DNA REPLICATION Telomeres are double trouble Genomic stability is maintained because DNA damage and stalled replication forks trigger repair path- ways, whereas telomeres are thought to protect the ends of chromosomes from triggering such responses. However, a new study shows that telomeres actually require the dam- age machinery at two distinct points in the cell cycle. Several reports have suggested that the DNA damage machinery is required for telomere replication, so Verdun and Karlseder looked in more detail at the timing of replication and the proteins that are associated with it in human cell lines. They used chromatin immunoprecipitation (ChIP) of telomeric proteins in conjunction with a BrdU assay to show that replication occurs at two points in the cell cycle. Further ChIP analysis showed that a different DNA dam- age signal is triggered by telomeres at each of these points: in the first, stalled replication forks at telomeres are recognized as DNA lesions by the ATR (ataxia telangiectasia and Rad3 related)-dependent damage machinery; in the second, the blunt ends of replicating telomeres are recognized as double-strand breaks and the homologous recombination machinery is triggered by ATM (ataxia telangiectasia mutated)- dependent signalling. The authors used in vitro assays to show that the homologous repair machinery is required for producing the protective loops that character- ize a mature functional telomere. They therefore propose a two-step model of telomere processing in which, rather than being shielded from being recognized as damage, the DNA damage machinery has an essential role. Patrick Goymer ORIGINAL RESEARCH PAPER Verdun, R. E. & Karlseder, J. The DNA damage machinery and homologous recombination pathway act consecutively to protect human telomeres. Cell 127, 709–720 (2006) RESEARCH HIGHLIGHTS 6 | JANUARY 2007 | VOLUME 8 www.nature.com/reviews/genetics © 2007 Nature Publishing Group

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Page 1: Telomeres are double trouble

Mapping QTLs in the mouse is important for determining the genetic basis of complex traits in mice and humans, and mapping QTLs to a high-enough resolu-tion to select candidate genes requires fine-scale maps. Now, Sagiv Shifman, Jonathan Flint and colleagues have produced a genetic map of the mouse genome using more than 10,000 SNP markers, making this the highest-resolution genetic map for any organism except humans. As well as being a useful mapping tool, this map provides a detailed picture of patterns of recombina-tion across the mouse genome.

In fact, the authors have pro-duced several SNP maps — one using an outbred population of 2,300 mice (resulting in separate maps for males and females), and another using eight sets of recombinant inbred lines (a total of 273 lines). Genetic maps describe the relative positions

of markers across the genome according to how often recombi-nation events occur between them. By comparing their SNP maps with a physical map of the mouse genome (the genome sequence itself), the authors pro-duced a picture of the density of recombination events across the genome.

In humans, recombination is known to evolve rapidly on a small scale (there is little correlation between the positions of recom-bination hotspots in human and chimpanzees), but recombination patterns on a larger scale seem to be more constrained. The authors examined the regions of recombi-nation ‘deserts’ (in which there is low recombination) and ‘jungles’ (regions of high recombination, including recombination hotspots). They show that several factors that are known to predict recombina-tion rates in human genomes also predict recombination

M O U S E G E N O M I C S

Crossing the map

In the 1930s, Dobzhansky and Muller — two pioneers of fly genetics — proposed that hybrid incompatibilties that contribute to speciation are caused by interactions between genes that have functionally diverged between the hybridizing species. Seventy years later, Daniel Barbash and colleagues have identified the first such pair of genes that cause male lethality in crosses between two Drosophila species. One of the partners encodes a protein that localizes to a heterochromatic region, and the authors suggest that the rapid evolution of sequences in this region has driven the evolution of the incompatibility gene.

Several genes that contribute to speciation are known, but none fulfils the three Dobzhansky–Muller

criteria: reduced fitness of the hybrid; functional divergence between the two hybridizing species; and dependence of a pair of genes on each other to cause their incompatibility effects.

No male flies are produced in crosses between Drosophila melanogaster females and Drosophila simulans males. It was previously shown that the Lhr1 mutation in D. simulans and a mutation in Hmr in D. melanogaster suppress this lethality, and genetic interaction studies hinted that there was something ‘Dobzhansky–Mullerian’ about this behaviour. Hmr is known to be X-linked and to encode a rapidly evolving DNA-binding protein with an MADF domain. The authors used a combination of mapping and candidate-gene approaches to clone the Lhr gene

E VO L U T I O N

The first Dobzhansky–Muller pair

…not only are recombination patterns well conserved on a large scale, they are influenced by similar chromosomal and sequence characteristics across mammals.

D N A R E P L I C AT I O N

Telomeres are double troubleGenomic stability is maintained because DNA damage and stalled replication forks trigger repair path-ways, whereas telomeres are thought to protect the ends of chromosomes from triggering such responses. However, a new study shows that telomeres actually require the dam-age machinery at two distinct points in the cell cycle.

Several reports have suggested that the DNA damage machinery is required for telomere replication, so Verdun and Karlseder looked in more detail at the timing of replication and the proteins that are associated with it in human cell lines. They used chromatin immunoprecipitation (ChIP) of telomeric proteins in conjunction with a BrdU assay to show that replication occurs at two points in the cell cycle. Further ChIP analysis showed that a different DNA dam-age signal is triggered by telomeres at each of these points: in the first, stalled replication forks at telomeres are recognized as DNA lesions by the ATR (ataxia telangiectasia and Rad3 related)-dependent damage machinery; in the second, the blunt ends of replicating telomeres are recognized as double-strand breaks and the homologous recombination machinery is triggered by ATM (ataxia telangiectasia mutated)-dependent signalling.

The authors used in vitro assays to show that the homologous repair machinery is required for producing the protective loops that character-ize a mature functional telomere. They therefore propose a two-step model of telomere processing in which, rather than being shielded from being recognized as damage, the DNA damage machinery has an essential role.

Patrick Goymer

ORIGINAL RESEARCH PAPER Verdun, R. E. & Karlseder, J. The DNA damage machinery and homologous recombination pathway act consecutively to protect human telomeres. Cell 127, 709–720 (2006)

R E S E A R C H H I G H L I G H T S

6 | JANUARY 2007 | VOLUME 8 www.nature.com/reviews/genetics

© 2007 Nature Publishing Group