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Volume 86, Issue 6:  June 11, 2010
(Next issue:  July 9, 2010)

In 1981, Martin Evans and Matt Kaufman reported that they had successfully established cell culture lines of mouse cells that were able to develop into any type of cells (Nature 292, 154–156). In 1984, with the help of additional colleagues, they injected these pluripotent embryonic stem cells into mouse blastocysts and demonstrated that the cells could incorporate into the germline and contribute to the development of chimeric mice (Nature 309, 255–256). This opened the door for the possibility of deliberately introducing desired genetic material into a mouse line. Such a process was first accomplished via retroviral infection, but the ability to specifically replace a gene with a modified version was not possible until techniques utilizing homologous recombination were refined. In 1985 and 1986, the groups of Oliver Smithies and Mario Capecchi, respectively, demonstrated homologous recombination in cell culture (Nature 317, 230–234; Cell 44, 419–428). The groups then made the leap toward modifying mice by successfully performing homologous recombination in Evans's mouse ES cells in 1987 (Nature 330, 576–578; Cell 51, 503–512). By 1989, the groups of Melton, Smithies, Jaenisch, and Capecchi had harnessed this technology and produced the first lines of knockout mice (Cell 56, 313-321; PNAS 86, 8927–2931; Nature 342, 435–438. Nature 346, 847–850). For their work, Capecchi, Evans, and Smithies received the Nobel Prize in Physiology or Medicine in 2007. On the cover is a redrawing of Figure 1 describing the gene-targeting technique used by Thomas and Capecchi in Cell 51, 503–512, against a backdrop of a chimeric mouse. Reprinted with permission from Elsevier.

Latest Articles

The American Journal of Human Genetics publishes papers online ahead of the print issue on a weekly basis. This week's postings include a report by Walsh et al. in which the authors use exome sequencing to identify a mutation in GPSM2 that causes hearing loss, a paper by Walsh et al. about a duplication that causes age-related hearing loss, a manuscript by Isidor et al. that describes deletions on 8q that cause mesomelia-synostoses syndrome, and an article by Duffy et al. about their GWAS for nevus count.

Click here to see all papers published early online.

Featured Article


Abraham's children in the genomic era
Time and geographic distance have raised the question of whether current Jewish communities around the world share more than a religious background. Here, Atzmon and colleagues tackle this question through their genome-wide analysis of seven distinct contemporary Jewish populations. Comparing the genetic profiles of these Jewish populations with those of non-Jewish people from the same regions, this group is able to identify distinct genetic patterns. While the different Jewish populations can be distinguished genetically, they can also be separated from non-Jewish populations, indicating that contemporary Jews share both religious and genetic history.

In This Issue


Nonrecurrent rearrangements in CMT1A and HNPP
The neuropathies Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) are caused by genomic rearrangements of 17p12. Although the vast majority of the 17p12 rearrangements are recurrent and due to nonallelic homologous recombination mediated by low-copy repeats, there is a subset of cases that are unique disruptions of atypical size. To learn more about these nonrecurrent rearrangements, Zhang and colleagues characterize the breakpoint sequences in a collection of such cases.


Controlling for population stratification in mtDNA association studies
The wealth of ancestry information contained in mtDNA is often utilized in population studies, but its presence also requires that steps be taken to control for hidden population substructure when mtDNA is used in association studies. A number of methodologies have been developed to handle population stratification (PS) in autosomal data, but less focus has been given to ways to correct for PS when using mtDNA. In this issue, Biffi and colleagues perform a comprehensive analysis of the effects of PS in mtDNA association studies and evaluate the best strategies for controlling it.


A definitive haplotype map of the Asian population
Determining CNV status by using SNP data is often complicated by the diploid and heterozygous character of the human genome; the phase of the SNP data must be inferred in order to establish the nature of the CNVs. Complete hydatidiform moles (CHMs) are a source of DNA that can bypass this issue. CHMs are products of conception in which all the genomic DNA is contributed by a single parent, and the tissue can be homozygous across the genome. In this issue, Kukita and colleagues present their characterization of the CNV structure of CHMs from the Japanese population. Their data are collected to produce a definitive map of the SNP and CNV haplotypes of these samples.


UFS is caused by HPSE2 mutations
Urofacial syndrome (UFS) is an autosomal-recessive disorder characterized by urinary and facial phenotypes. If left untreated, UFS can result in kidney failure. In this issue, Pang and colleagues and Daly and colleagues independently perform homozygosity mapping and sequence analysis on a number of ethnically diverse UFS patients. Both groups identify causative HPSE2 mutations in their patients. This work points to a role for heparatinase 2 in this potentially lethal condition.

Featured Article from Trends in Genetics

The genetics of obesity: FTO leads the way

In 2007, an association of SNPs in the fat mass and obesity-associated (FTO) gene region with body-mass index and risk of obesity was identified in multiple populations, making FTO the first locus unequivocally associated with adiposity. At the time, FTO was a gene of unknown function, and it was not known whether these SNPs exerted their effect on adiposity by affecting FTO or neighboring genes. Therefore, this breakthrough association inspired a wealth of in silico, in vitro, and in vivo analyses in model organisms and humans to improve knowledge of FTO function. These studies suggested that FTO plays a role in controlling feeding behavior and energy expenditure. Here, Fawcett and Barroso review the approaches taken that provide a blueprint for the study of other obesity-associated genes in the hope that this strategy will result in increased understanding of the biological mechanisms underlying body-weight regulation.

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