Nature Genetics pp 305 - 308

The mouse has proven, time and time again, to be an invaluable genetic model. Nowhere is this more apparent than in the study of disease, where hundreds of conditions have been modelled and potential treatments explored. Similarly, mouse models show great promise for unravelling the genetic basis of behaviours, but the dissection of traits such as mood, personality and intelligence has proven more difficult, as behavioural variation is often subtle and the influence of genetic components difficult to measure.

The first step in identifying a gene corresponding to a trait is to identify its approximate position on one of the chromosomes -- a process called 'genetic mapping'. All maps require road signs; the more signs, the easier it is to locate the target. The 'road signs' in the mouse genome are genetic markers. The most effective way to map a gene for a particular trait is to identify a linked genetic marker and search the surrounding chromosomal region for the gene of interest. Normally, this is done by crossing two distinct inbred mouse strains that have different markers and looking for a marker that is inherited with the trait. For mapping studies, outbreeding is usually carried out for only two generations (each requiring approximately 2-3 months), but at this point, the detail is often not high enough to be informative.

To add more detail to the mouse map, Jonathan Flint (of the Institute of Molecular Medicine) and colleagues use a stock of mice outbred for 58 generations and for which the entire genealogy is known. This mouse population was established 30 years ago from crosses between eight inbred mouse strains. The researchers show that crossing out-bred mice offers a dramatic increase (about 30-fold) in map resolution over that provided by second-generation crossing of different inbred mice. The researchers demonstrate the efficacy of their method by conclusively linking two behavioural traits in the mouse associated with anxiety to narrow intervals on mouse chromosomes 1 and 12. The high resolution made possible with this approach will allow easier identification of these and other genes underlying subtle behavioural traits in a model system, and should lead to novel insights into the genetic basis of behaviour in humans.

Nature Genetics pp 289 - 292 and pp 253 - 254

There are few cells as physically stunning as the 'hair cells' of the inner ear. Each cell has two rows of long appendages that resemble hairs (called stereocilia) that protrude from its surface -- each row is shaped like a gentle 'V', with one row slightly longer than the other. Towards the tips of the stereocilia are tip links, tiny bridges that link the ends of the cilia of the taller row with those of the shorter row. The stereocilia abut against a fairly rigid support called the tectorial membrane. Physical movement of the hairs against this membrane, which occurs when waves oscillate through the fluid of the inner ear, is translated into 'electrical' information by the hair cells, and transmitted to the brain.

As one might imagine, the integrity and function of hair cells are critical to one's ability to hear properly; previous studies have shown that mutations in genes encoding some of its components (and that of the tectorial membrane) result in deafness. The molecular 'building blocks' known to govern hair cell formation and function are also few and far between. Matthew Kelley and colleagues, of the Georgetown University School of Medicine, now report that two molecules previously implicated in determining cellular fate -- Notch and jagged-2 -- have seminal roles in hair-cell development. They concluded this upon observing that mice without jagged-2 have a significant increase in hair cell density, compared with normal mice. These mice also appear to have fewer supporting cells -- cells that are usually interspersed with hair cells. Kelley and colleagues also observed that jagged-2 is expressed by nascent hair cells of normal mice whereas Notch is expressed in supporting cells. These observations suggest that the Notch receptor extends from the supporting cell and inhibits, through its binding to jagged-2, hair-cell development in the normal mouse.

Because the Drosophila counterparts of Notch and jagged-2 have been demonstrated to mediate sensory bristle development, it has been suggested that the Drosophila bristle and the mammalian ear share a common evolutionary origin. On the other hand, as James Posakony (of the University of California) argues in an accompanying News & Views article, without 'accessory' evidence from other molecules and considering the widespread 'popularity' of Notch-signalling for determining cell fate, it may be premature to draw such conclusions. But as he also notes, it is nonetheless satisfying to get at one of the roots of the magnificent mechanosensory mosaic comprised by the inner-ear hair cells.

Nature Genetics pp 258 - 259

Birds and humans went their separate ways -- evolutionarily speaking -- about 300 million years ago. Since then, their 'sex' chromosomes have diverged to the extent that each species appears to have a different system for determining sex. Human females have two 'X' sex chromosomes, and are therefore called the homogametic sex. Human males have an 'X' and a 'Y' sex chromosome, making them the heterogametic sex. Conversely, female birds are the heterogametic sex (they carry 'Z' and 'W' chromosomes) and the males, carrying two 'Z' chromosomes, are homogametic.

Some years ago, it was discovered that the mammalian Y chromosome carries a gene (called SRY) which is a major sex determinant -- female mice engineered to carry Sry develop testes, the signature feature of the mammalian male. There are, however, genes that operate downstream of SRY that also affect sexual characteristics; one of these appears to lie on chromosome 9, because XY human males who have a deleted portion of this chromosome fail to develop testes and exhibit sex reversal. It would seem that the gene or genes on this portion of chromosome 9 are 'dosage' sensitive -- or rather, the sexual characteristics that they affect are dependent on the dose. Inherit two copies and one develops testes; inherit one, and one does not. In contrast with the human condition, the genetic determination of sex in birds is obscure. The avian equivalent of SRY does not exist; in fact, there are no known genes that determine sex in birds.

Upon comparing the chicken genome with the human genome, however, Michael Schmid and colleagues (of the University of W¸rzburg, Germany) have not only uncovered the largest region of chromosomal conservation since the avian and mammalian lineages diverged; they also pinpoint an excellent candidate for avian sex determination -- a gene called DMRT1. Schmid and colleagues found that a stretch of genes that lie along the chicken 'Z' sex chromosome are highly similar to those of human chromosome 9, although (as would be expected) a certain degree of 'gene shuffling' has occurred. Human and chicken versions of DMRT1 lie within this region. Other studies have shown that human DMRT1 is expressed in the testes and its structure is similar to sex-regulatory genes in flies and worms. If DMRT1 turns out to be a or the critical gene that underscores sex reversal in humans who lack the relevant portion of chromosome 9, it stands to reason that it may also affect sex determination in birds -- as females carry one copy of the Z chromosome, while males carry two. While it's clear that sex isn't just for the birds, birds may end up telling us something about sex.