Imperial College London

A population geneticist looks back in time in search of human origins.

When and where anatomically modern humans evolved is arguably one of the most fundamental scientific questions. The issue also has philosophical and possibly even moral implications because it influences our definition of humanity. But I became involved in the subject for much more prosaic reasons. I was trying to make sense of the distributions among human populations of different versions of genes that imbue resistance to infectious diseases. It struck me that attempting to do this without a clear understanding of humans' past demography was bound to end in a muddle.

Despite decades of research, the origin of modern humans is still hotly debated. In a recent paper, Laurent Excoffier and his colleagues provide the first formal statistical evaluation of the likelihood for the various schemes that have been proposed (N. J. R. Fagundes et al. Proc. Natl Acad. Sci. USA 104, 17614–17619; 2007). They conclude that a recent expansion from a single African origin is better supported by the current geographical spread of human genes than a multi-regional scenario. The multi-regional hypothesis proposes that modern humans hybridized with archaic humans, such as Homo erectus, as they spread.

This result may seem unsurprising because most genetic evidence points to an African origin some 60,000 years ago with no or negligible hybridization with archaic humans. However, there is a twist. By far the best supporting evidence for hybridization between modern and archaic humans has been the observation that, looking back, the amount of time it takes to reach the most recent common ancestor of some genes largely predates the age of our species. The extensive simulations in this paper debunk that argument by demonstrating that such cases can arise if modern humans had a recent and single African origin.

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University of Helsinki, Finland

A statistician wonders about the influence of additive variance

Where complex problems are concerned, it makes things simpler if some factors can be safely ignored. In quantitative genetics, one such assumption is that the bulk of genetic variation is additive. That is, the effect of an allele — a particular version of a gene — can be adequately described by its average effect in a population. But we know that genes often do not act additively; alleles interact, both with others of the same gene (a phenomenon known as dominance) and those of different genes (epistasis). All this contributes to the total genetic variation. But does this matter?

This question is tackled by Hill et al. (PLoS Genet. 4, e1000008; 2008). Reviewing the literature, they show that additive genetic variance is often close to total genetic variance. The authors then look at some mathematical models with strong non-additive genetic effects, and average over reasonable distributions of allele frequencies to show that the genetic variance is mainly additive. So non-additive genetic variation is usually of minor significance and we can continue to concentrate on additive genetic variance.

This is probably true on average, but may not always be so. Any trait is affected by only a finite, and in some cases small, number of genes. So averaging over all possible allele frequencies may say little about a particular case. There is also a much subtler problem. The authors conclude that additive genetic variance swamps other types of variation largely because most alleles common to a population occur with close to 100% frequency. But these extreme frequencies also reduce the total genetic variance. So, in practice, a lot of traits with strong additive effects might be classified as having no detectable genetic variation, and overall the importance of additive genetic effects would be diminished. Is this a genuine problem? Ah, more research is obviously needed.

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Queen's University, Belfast, Northern Ireland

A chemist looks at DNA-based molecular logic

Logic gates — AND, OR and NOT gates — are used in all manner of electronic devices, for example computers, in which they are connected in huge arrays. Several research groups, including my own, have designed and built molecular logic gates since the early 1990s. But the usefulness of our efforts has been limited because linking these gates in series has proved difficult.

Recently, Reza Ghadiri and his colleagues at the Scripps Research Institute in La Jolla, California, constructed a full set of logic gates that release a single-stranded DNA sequence when provided with the correct combination of single-stranded DNA inputs (B. M. Frezza et al. J. Am. Chem. Soc. 129, 14875–14879; 2007). This means that the output of one gate can be the input for another, and that the gates can be 'wired together' into multi-level circuits using the solution containing the DNA as a communication medium.

The gates work as follows. When a single strand of DNA pairs with a longer strand, an 'overhang' of unpaired DNA is left. If another complementary strand then comes along that is the same length as the longer strand, the overhang provides a foothold, allowing the new strand to push the shorter one off and form a full-length hybridized pair. Ghadiri et al. attached the DNA to beads so that different gates could be kept apart until the correct input was ready. They also added a fluorescent part to the final output signal to make the result easy to monitor.

This may not seem like much of an achievement to a computer buff. Nevertheless, I think the principle that this paper describes could pave the way to more useful molecular logic gates. In the meantime, the simple molecular logic gates that are available can serve in real-life applications such as identification tags for small micrometric objects. Semiconductor identification devices are too big for this purpose.

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Howard Hughes Medical Institute, University of Pennsylvania, USA

A geneticist reflects on DNA sequence variants that influence gene expression and disease risk.

Most people are familiar with the Human Genome Project and the HapMap, which catalogued the millions of DNA-sequence differences among humans. But which of these differences influence our risk of developing diseases remains unclear. This is particularly true for disorders such as heart disease that involve not only many genes but also the interactions among them. In addition, the effects of variations in DNA sequence are often subtle, such as altered levels of gene expression. Identifying those DNA sequences that determine levels of expression across individuals could have great medical potential.

One paper that illustrates this point looks at the two major contractile proteins of the human heart, the - and -forms of the myosin heavy chain (E. van Rooij et al. Science 316, 575–579; 2007). Here, Eric Olson and his team at the University of Texas in Dallas identify a microRNA, called miR-208, that regulates how much of the -form heart cells produce.

A healthy heart requires a particular ratio of - and -heavy chains for its cells to function normally. When stressed, heart cells tend to make too much of the -form, causing the organ to enlarge, replete with fibrous connective tissue, and less able to contract. This often happens in people with heart disease.

In finding miR-208, the researchers have determined a key component in the molecular basis of heart failure. The next step might be to look for sequence variants of miR-208 and of other gene-expression regulators that could explain why some people are more susceptible to heart disease than others. In this way, whole biological networks could be pieced together and common medical problems more fully understood.

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University of Chicago, Illinois, USA

An evolutionary geneticist is surprised by genes of unknown origin.

I once thought that, like us, every gene must have a mother. But recent work has identified some genes that seem to have no genetic ancestry. These 'motherless' genes pose a new challenge to understanding the molecular mechanisms and evolutionary forces that shape our DNA. This isn't the first time we've had to revise our ideas about gene evolution.

About 40 years ago, geneticist Susumu Ohno proposed that new genes originate when an existing gene duplicates, then one of the copies evolves a new function. Working with Chuck Langley in the early 1990s, I had the luck to discover a gene in flies that added another strand to Ohno's story. The gene, named Jingwei, is a chimaera that formed through the combination of two existing genes.

Since then, researchers have identified many other 'new' genes assembled from unrelated genes and mobile DNA elements. Often the sequences' origins can be identified. When they can't, researchers have simply assumed that subsequent evolution has masked the relationship of the gene to its ancestral sequences.

But this is unlikely to be the case for hydra, a gene found recently in Drosophila melanogaster and closely related species (S.-T. Chen et al. PLoS Genet. 3, e107; 2007). No homologous sequences are found in a species that diverged from those carrying hydra only 13 million years ago — too recently for mutations to have obscured any related sequences. This implies that hydra arose de novo.

Another group has found a further 16 de novo genes in flies, which they propose evolved from non-coding DNA (D. J. Begun et al. Genetics 176, 1131–1137; 2007 and M. T. Levine et al. Proc. Natl Acad. Sci. USA 103, 9935–9939; 2006). These genes beg further study: what initiated their formation?

Editor's Note, the entry previously misspelled the name of the author's institution. Nature regrets the error.

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Collegium Budapest, Hungary, and The Parmenides Foundation for the Study of Thinking, Munich, Germany

A theoretical biologist recommends thought-provoking reading on the origin of translation and the genetic code.

As Francis Crick and his co-workers once noted, "the origin of protein synthesis is a notoriously difficult problem". Our best hopes of resolving this problem begin, in my opinion, in an RNA world.

The RNA-world hypothesis holds that RNA emerged before DNA and proteins, neatly separating the origin of life from that of the genetic code and its translation. The question then becomes: how did RNA evolve to make proteins?

In a recent paper, Yuri Wolf and Eugene Koonin of the National Institutes of Health in Bethesda, Maryland, present one scenario (Biol. Direct 2, 14; 2007).

They rightly call attention to studies that suggest that protein-based aminoacyl-tRNA synthetases, which are involved in the first steps of assembling amino acids into proteins, are relatively late evolutionary inventions. This forces us to accept the idea that protein synthesis is older than such synthetases.

Before the evolution of synthetases, the only agents that could conceivably have marshalled amino acids are RNA enzymes, or ribozymes. Wolf and Koonin share my view that the recruitment of amino acids was driven by selection for enhanced catalytic activity, and that the ancestor of the large ribosomal RNA that catalyses protein synthesis in today's cells — a molecular 'fossil' — was a catalyst that linked only two amino acids.

I am less happy with these authors' suggestion of a relatively late switch from peptide-specific proto-ribosomes to those that could use an external template such as mRNA to synthesize peptides with arbitrary sequence — but they may well be right.

They lay out an evolutionary sequence that is more complete than the scenario I once proposed. I highly recommend this well-written, thought-provoking paper.

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University of California, San Francisco, USA

To an epigeneticist, cancer is encrypted in genes and their packaging.

Early in my career I had the good fortune to study epigenetics in a lab focused on the molecular genetics of cancer. At the time, geneticists typically thought that in cancer, epigenetic changes — which affect regulation of the genome but not the genome's sequence — were epiphenomena less worthy of study.

This might have made the experience akin to being a Republican mayoral candidate in left-leaning San Francisco; instead it was positively transforming.

As my own research group took shape, I began to integrate genetic and epigenetic theories of malignant transformation. Now, hereditary human cancers and genetically engineered mice once held up as evidence for genetic models also provide evidence for epigenetic models, and we study the interactions of the two mechanisms.

In this light, a recent paper (G. G. Wang et al. Nature Cell Biol. 9, 804–812; 2007) captured my attention because it dissects how one genetic change leads to epigenetic changes that ultimately cause leukaemia.

The work focuses on an abnormal fusion protein — produced after part of one gene fused, or translocated, with part of another — and narrows down its cancer-causing properties to a particular region of the protein. This region mediates an epigenetic change: it adds a methyl group to one amino acid of a histone, part of a gene's packaging in the nucleus.

The team found that the fusion protein misdirects its methylation to the histones that package HoxA genes, triggering further miscoding of the histones. This activates the genes, which promote self-renewal of blood-cell precursors, contributing to leukaemia.

I wonder if the interactions could be traced back even further. Given the role of epigenetics in stabilizing chromosomes; might it have been epigenetic miscoding that made the gene susceptible to translocation in the first place?

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New York University, USA

An evolutionary geneticist wonders why certain crops were 'invented' not once but multiple times.

Crop species have always captured my imagination — perhaps because Darwin saw domestication as a model for the evolutionary process, or maybe because I am an inveterate foodie. Whatever the reason, I work on the evolution of crop species as diverse as rice, barley and cauliflower, using genomic methods to trace their origins.

I was struck by two recent molecular studies that indicate that key crops may have evolved more than once in association with different cultures, after Neolithic farmers began to cultivate various wild plants and select desirable traits 12,000 years ago.

Rice seems to have originated from the wild rice Oryza rufipogon separately in China and in India and southeast Asia (J. P. Londo et al. Proc. Natl Acad. Sci. USA 103, 9578–9583; 2006). Meanwhile, barley, which originated once in the Fertile Crescent — a region defined by an arc through Lebanon, Syria, Turkey and Iraq, and home to the oldest archaeological evidence for agriculture — may also have had a second origin in present-day eastern Iran (P. L. Morrell and M. T. Clegg Proc. Natl Acad. Sci. USA 104, 3289–3294; 2007).

Previous genetic mapping studies of the loss of seed shattering in rice and barley suggests that the trait is controlled by different genes in different lineages of these crops. This makes sense in the light of a multiple-origins scenario.

The pattern is not unique — cattle, sheep and goats were also domesticated multiple times. So did different cultures learn how to go about domesticating wild plants and animals from each other, or did they arrive at the same evolutionary solutions independently when faced with similar challenges? Hopefully the genetic data will motivate archaeologists to dig for evidence of how groups of people went about developing these crops.

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University of California, San Francisco, USA

A cancer geneticist delves into family matters.

A mystery lies at the heart of a small family of growth signalling enzymes (K-Ras, H-Ras and N-Ras), which are widely mutated in human cancers. In culture, all three enzymes have similar functions, but different ras genes are associated with cancers in different tissues.

My laboratory, for instance, noted more than 25 years ago that skin cancers show activation of H-ras. Others have demonstrated that lung, colon and pancreatic cancers show activation of K-ras, whereas N-ras is the oncogene of choice in melanomas and some leukaemias.

What determines this intriguing specificity? Are the enzymes' functions somehow modified in certain tissues in vivo? Or is it regulation of the genes, affecting where and when they are expressed, that matters?

We may get some answers by following the lead of an elegant study (N. Potenza et al. EMBO Rep. 6, 432–437; 2005). In this work, the authors knocked out K-ras in mice, but simultaneously replaced the gene with its close relative H-ras, doctored to have the regulatory elements of K-ras. Mice can survive without the H-ras or N-ras genes (or even both of them) but usually die if K-ras is deleted. These mice, despite lacking K-ras, were viable and lived to a ripe old age.

This important observation provides novel opportunities to probe the mechanisms of cancer initiation. Are the mice lacking K-ras now resistant to the lung and pancreatic cancers that are normally linked to K-ras? If yes, this would indicate a true requirement for the K-Ras protein in lung-cancer development; if not, the focus would switch to regulation.

A straw poll of Ras cognoscenti suggests that opinion is for now divided, but my group and others are working on this mouse model, and hope to have answers soon.

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Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts

A geneticist rebuts criticism of cancer genome projects.

What do you learn if you sequence 13,000 genes in 11 breast and 11 colorectal cancer samples? The question taps into an intense debate about how best to identify genes relevant to human cancer.

Last year, researchers reported the results of a survey such as the one described (T. Sjöblom et al. Science 314, 268–274; 2006). They found that each tumour contains, on average, 90 mutant genes — an unexpectedly high number. They also defined mutation spectra that were specific to colon and breast tumours, including the intriguing observation that the DNA letter sequence CG was swapped for GC at high frequency in breast tumours. This could be due to an uncharacterized DNA repair defect or differential carcinogen exposure.

I consider this report a step towards answering key questions in cancer biology, such as how many genes are mutated in cancer, how many mutations are required for cancer, and whether accumulation of genetic alterations in cancer cells drives tumour progression.

But others disagree. Many labs see large-scale sequencing of cancer genomes as unfocused and expensive fishing experiments. I have been doing genomics experiments since the dawn of this era, and have often faced this criticism.

But just this one study has identified more genes mutated in human cancer than thousands of investigators have found over past decades. And another recent, large-scale sequencing project pinpointed close to 120 mutant kinase enzymes that may have a role in human cancers (C. Greenman et al. Nature 446, 153–158; 2007).

Both cases show that the outcome of unbiased, genome-wide studies may not be what we expect, which is exactly why they're worth doing.

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Harvard University, Cambridge, Massachusetts, USA

Thanks to the discovery of a new catalytic RNA, a chemical biologist can satisfy his student's curiosity.

An first-year undergraduate recently asked me a remarkable question: are all natural ribozymes, RNA molecules with catalytic activity, simply leftovers from the 'RNA world'? The RNA-world hypothesis supposes that RNA molecules were precursors to the first primitive forms of life, before the evolution of DNA and proteins.

Unanswered, my student's question preoccupied me until I encountered a recent paper by Jack Szostak of Massachusetts General Hospital, Boston, and his co-workers (K. Salehi-Ashtiani et al. Science 313, 1788–1792; 2006).

Prior to this work, only two of the known natural ribozymes were associated with mammals. The rarity of catalytic RNAs in more recently evolved, higher-order cells could reflect their attrition on the evolutionary battlefield during the rise of more highly functional protein enzymes.

This paper, however, supports a different conclusion. Szostak's group designed an ingenious system to isolate self-cleaving RNA molecules from RNA encoded in the human genome. Using this system, they discovered several new ribozymes.

One of these ribozymes, associated with a gene known as CPEB3, is highly conserved among placental mammals and marsupials, but is absent from non-mammalian vertebrates. This observation suggests that it arose relatively recently, around 200 million years ago.

We can therefore infer that some ribozymes have evolved in modern organisms, long after the era of the RNA world. The work elegantly demonstrates a new approach to the study of ancient molecules — and also reminds me that our youngest students can ask some of the best questions.

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