Nature Genetics pp 348 - 353 and pp 253 - 254

Retroviruses insert at random sites in the genome of a host animal, sometimes causing disruption of a gene, which can lead to cancer. Researchers have used these viruses as ëtagsí to identify candidate cancer genes, but methods to identify the sites where retroviruses insert are slow and laborious. Neal Copeland (NCI-Frederick Cancer Research & Development Center) and colleagues have devised a strategy for speeding up this process -- and they report the identification of nearly 100 candidate genes for leukaemia, many of which have never been implicated before.

Certain mouse strains are prone to developing leukaemia, a process that is accelerated when a retrovirus ëhitsí a cancer-associated gene. Copeland and colleagues infected such mice with retroviruses, and selected those with accelerated leukaemia. They then isolated the genomic region containing the inserted viral DNA as well as the adjacent mouse sequence and determined the sequence of more than 400 such insertion sites (some of which represent genes ëhití more than once). They compared these sequences with those stored in public sequence databases and identified scores of candidate cancer genes. Some of these are known to play a role in cancer in mice and humans -- thereby validating the authorsí approach -- whereas others potentially reveal new pathways involved in cancer.

As discussed by Ronald DePinho and Tyler Jacks in an accompanying News & Views article, the work underscores how high-throughput genomic technologies can speed up the rate of discovery in cancer genetics. The next step -- validation of these candidate genes as being involved in cancer -- is also amenable to rapid high-throughput screening, thanks to the sophisticated tools available for manipulating the mouse genome. Furthermore, using strains of mice prone to other types of cancer, this strategy could also be used to identify genes involved in tumour formation in different tissues.

Nature Genetics pp 314 - 318 and pp 254 - 256

Genes influence the way we look -- and variations in gene sequences can account for the differences between individuals. Family traits are often credited to (or blamed on!) gene variants that are passed down through generations of families. But a report by Emma Whitelaw (of the University of Sydney) and colleagues now suggests that gene sequence may not be the only thing we inherited from our parentsí genomes. They show that alterations that change the expression but not the sequence of genes -- known as epigenetic modifications -- can be inherited in mammals.

An epigenetic modification is a ëmarkí present on some genes that determines whether the gene is expressed (switched on) or ësilentí. Animals are thought to acquire this mark during development, and it is retained throughout life, except in the germ cells (which are progenitors of sperm or eggs), where the mark is erased. Erasing the imprint in the germ line ensures that the next generation has a ëclean slateí with respect to epigenetic modifications, and that only truly genetic traits (those encoded by the actual sequence of the DNA) are inherited.

Emma Whitelaw (of the University of Sydney) and colleagues challenge this view; they present evidence that, in the mouse germ line, not all epigenetic marks are completely erased. The authors studied the inheritance of coat colour in mice. They found that, independent of the sequence of the coat colour gene, the motherís coat colour influences the likelihood of the pups having the same colour coat. For instance, a yellow mother has more pups that are yellow than mottled, whereas a mottled mother is likely to have a higher percentage of mottled pups. But the gene that determines the coat colour has an identical sequence in both the yellow and mottled mothers, so something else must be coming from the mother to influence coat colour. Whitelaw and colleagues show that an epigenetic mark located at the start of the gene is responsible; it influences the expression of the gene, which in turn determines the colour of the coat. Instead of being completely erased in the motherís germ line, this epigenetic mark is passed on to subsequent generations, where it exerts an influence on coat colour.

Although the inheritance of epigenetic modifications has been previously reported in plants, yeast and flies, this is the first convincing evidence in mammals. Azim Surani and Rosalind John (of the University of Cambridge) discuss, in an accompanying News & Views article, how epigenetic marks might escape erasure and be passed through the germ line to influence the characteristics of subsequent generations. As many regions of the mammalian genome are subject to epigenetic alterations, it is possible that these modifications may have a major influence on the variation among individuals -- including differences in susceptibility to disease.

Nature Genetics pp 309 - 313

Malaria kills nearly 2 million people every year and is caused by the single-celled parasite Plasmodium falciparum. Devising ways to effectively treat and prevent malaria has been a persistent challenge, but sequencing the P. falciparum genome -- the goal of the Malaria Genome Consortium -- is expected to reveal insight into the biology of the parasite and help in the development of new methods to combat malaria.

The genome of P. falciparum consists of 14 chromosomes, each of which consists of a very long stretch of DNA. Rather then starting to sequence at one end of a chromosome and continuing through to the other, the DNA must be broken into small (overlapping) fragments, whose sequence is determined individually. The sequences of the overlapping fragments then need to be assembled in the correct order. This jigsaw puzzle is the most difficult step of any sequencing project -- but it is made much easier if a ëmapí of the genome is available.

A team of researchers at the University of Wisconsin-Madison and New York University has now created a map for the whole genome of P. falciparum. Making a genome map typically involves constructing a rough ëblueprintí from existing data, but in the case of P. falciparum, relatively little is known about its genome. The authors overcame this problem by using so-called ëoptical mappingí, a technique they pioneered and previously used on much smaller organisms. To generate an optical map, the genome is broken up into large fragments and ëpinned downí on a solid surface. The stretched, immobilized DNA threads are then treated with a restriction enzyme, a molecular ëscissorí that cuts at specific places in the DNA, to generate smaller fragments which remain attached to the slide and whose length is measured using digital imaging. Different restriction enzymes cut at different places, thereby generating distinct patterns of DNA fragments. Using specialized computer programs, the authors analysed these patterns to construct a map of the entire P. falciparum genome, with the DNA sites recognized by different restriction enzymes serving as ësignpostsí.

This report also illustrates how optical mapping can rapidly create a map of an organismís genome about which little is known. The map will expedite the sequencing of P. falciparum and has the potential to accelerate other sequencing projects, including that of the human genome.