Unit 9. Human genetics and diversity

Script 21. Evolution

The value of a good editor

A hitherto-unknown way to evolve.

In 1958 Francis Crick, one of the codiscoverers of the double-helical structure of DNA, spelled out what came to be called the "central dogma" of molecular biology. In a nutshell, this says that DNA makes RNA, which makes proteins. In other words DNA - which carries an organism's genetic code - "writes" that code into bits of RNA, a similar, but not identical molecule. These then act as messengers which tell a cell's protein-making machinery what to make.

It is a pithy and memorable summary. Sadly, reality is not quite so clear-cut. In a paper in Science, Sandra Garrett and Joshua Rosenthal of the University of Puerto Rico illustrate how the instructions in the DNA are not always followed faithfully. The RNA message can be rewritten before it is read. And that provides an extra opportunity for evolution to occur.

Dr Garrett and Ms Rosenthal were studying octopuses, looking for differences between those that live in warm, tropical water and those that inhabit the poles. They concentrated on the make-up of the ion channels in the animals' cell membranes. These channels are cylindrical assemblages of protein molecules which help to control such things as the electrical activity of nerve cells and the release of hormones. The two researchers suspected that the channels found in warm-water species would not work well in the freezing temperatures that their polar cousins endure.

That turned out to be correct. What was odd was that the genes for the proteins involved were almost identical in warm- and cold-water animals. This surprised Dr Garrett and Ms Rosenthal, who had expected that natural selection would have changed the DNA, and thus the composition of the resulting protein.

Instead, differences in composition between warm-water and cold-water ion channels were the result of a phenomenon called RNA editing, in which special enzymes alter the structure of the RNA messenger, and thus of the final protein.

Though RNA editing has been observed before, in animals ranging from humans to nematode worms, this is the first time an edit has been tied to a clear evolutionary difference caused by a feature of the environment - in this case ambient temperature. Of course, it is not strictly a departure from Crick's dogma. Enzymes, too, are proteins, and so are the transcription factors that regulate their production. Eventually, when the chain of causation is traced in full, the chances are that the underlying difference between polar and tropical octopuses will be in the DNA itself. RNA editing of this sort does, however, provide another way to drive evolution, and may help explain why animals (as opposed to, say, bacteria) are so complex. (From The Economist, January 7, 2012)

Script 22. The nature of man

The nature of man

Large-scale genetic studies are throwing light on what makes humans human.

Humans are peculiar as a species, so what makes them so must be hidden in their genome. To an almost disconcerting extent, though, the human genome looks similar to the genomes of other primates, especially when it comes to the particular proteins it allows cells to make. The powerful new ways of looking at the genome being pioneered by the ENCODE consortium, though, provide ways to seek out the subtle species-specific signals. Lucas Ward and Manolis Kellis of the Massachusetts Institute of Technology report on the results of such sleuthing in a paper just published in Science.

The two researchers used data from ENCODE to identify the bits of the genome that actually do things and data from the 1,000 Genomes Project, which has studied human-genome variation across hundreds of people, to discover how much these functional elements vary from person to person. In particular, they looked for telltales that an element is being maintained by natural selection. If something is evolutionarily important then random variations in its DNA sequence will be slowly eliminated from the population, keeping it on the functional straight and narrow in a process known as purifying selection.

Dr Ward and Dr Kellis found that, in addition to the 5% of human DNA that is conserved between mammals, an additional 4% of human DNA appears to be uniquely human in the sense that it is prone to purifying selection in humans but not in other mammals. Much of this proprietary DNA is involved in regulating gene activity - for example, controlling how much of a protein is produced, rather than changing the nature of the protein itself. This finding is in line with modern thinking that a lot of evolutionary change is connected with regulatory elements rather than actual protein structure. The researchers also found that long non-coding segments that are not conserved in other mammals are in fact highly constrained in humans, suggesting they have human-specific functions.

Some areas identified as particularly human are the regulation of the cone cells of the retina (which are involved in colour vision) and the regulation of nerve cell growth. These processes evolved rapidly in man's primate ancestors but are now under strong purifying selection to maintain their beneficial functions. The implications of that, given humanity's main distinguishing feature - its huge brain - are obvious. Dr Ward and Dr Kellis have thus created a powerful tool for investigating in detail just what it is that makes a human being human. (From The Economist, September 8, 2012)

Script 23. Tibetan genetics

Life at the top

The secret of Tibetans' success lies with ancestors who were not quite human.

Researchers have known for a while that many people alive today carry genes from human species other than Homo sapiens - the result of ancient interbreeding with Neanderthals and Denisovans. They have even worked out that this admixed DNA must often be doing something particularly useful, because its pattern suggests natural selection is actively retaining it. The specifics, though, have not been clear. But in one case they now are, for it is because of these occasional Denisovan ancestors that Tibetans thrive in Tibet.

The plateau of Tibet is one of the most hostile places people inhabit. The air is thin and the weather cold. The locals, nevertheless, do well. And Rasmus Nielsen of the University of California, Berkeley, and his colleagues at BGI, a Chinese DNA sequencing laboratory, suggest in this week's Nature that one of the genes which lets them do so is Denisovan.

The Denisovans are a mysterious branch of Homo. They were identified in 2010 by an analysis of the DNA of a bone discovered in a cave (occupied in the 18^th century by a hermit called Denis) in the Altai Mountains in Russia. This bone was thought, when found, to be either Neanderthal or modern human, but the analysis showed it was neither. In the wake of that finding, a small percentage of Denisovan DNA has been discovered in various groups of people in Asia and the Pacific islands, Tibetans among them.

The gene Dr Nielsen has been investigating is a version of EPAS-1. This encodes part of a protein called hypoxia-inducible transcription factor 2-alpha. Transcription factors activate other genes, and this one (as its name suggests) does so in response to low oxygen levels. When that happens, it is responsible for stimulating the production of red blood cells, the growth of capillaries and the production of proteins involved in energy generation.

Everybody has some version of EPAS-1, and so everybody can acclimatise to high altitude. But such acclimatisation comes at a price: the extra red cells make blood stickier and more likely to clot, which increases the risk of thrombosis. Except, curiously, in Tibetans. They are well acclimatised without having noticeably raised red-cell counts. And that effect has been tracked down to the particular version of EPAS-1 in their chromosomes.

Dr Nielsen and his team wanted to study the Tibetan version more closely, so they sequenced both it and the area around it in detail. When they did this they discovered that the block of DNA it inhabits is so similar to its Denisovan equivalent that it must originally have come from a mating (maybe more than one) between a Denisovan and Homo sapiens.

Moreover, it is pretty much only Tibetans who have this version of the gene. Dr Nielsen established in 2010 that about 90% of them do, compared with fewer than 10% of their Han Chinese neighbours. He estimated that the altitude-friendly version became this widespread in Tibet in a mere 3,000 years.

His latest study also looked at other groups with Denisovan genes, and could find no trace at all in them of the Denisovan form of EPAS-1. Probably, it is useless or worse at low altitudes, so natural selection has removed it. But, though the Altai Mountains are not as high as Tibet, it might well have been useful there. (From The Economist, July 5, 2014)

Script 24. Gene Therapy

Hello mothers, hello father

A technique intended to eliminate mitochondrial diseases would result in people with three genetic parents.

Is it possible for a child to have three parents? That is the question raised by a paper just published in Nature by Shoukhrat Mitalipov and his colleagues at Oregon Health and Science University. And the answer seems to be "yes", for this study paves the way for the birth of children who, genetically, have one father, but two mothers.

The reason this is possible is that a mother's genetic contribution to her offspring comes in two separable pieces. By far the largest is packed into the 23 chromosomes in the nucleus of an unfertilised egg. In that, she is just like the child's father, who provides another 23 through his sperm. But the mother also contributes what is known as mitochondrial DNA.

Mitochondria are a cell's power-packs. They convert the energy in sugar into a form usable by the cell's molecular machinery. And because mitochondria descend from a bacterium that, about 2 billion years ago, became symbiotic with the cell from which animals and plants are descended, they have their own, small chromosomes. In people, these chromosomes carry only 37 genes, compared with the 20,000 or so of the nucleus. But all of the mitochondria in a human body are descended from those in the egg from which it grew. The sperm contributes none. And it is that fact which has allowed doctors to conceive of the idea of people with two mothers: one providing the nuclear DNA and one the mitochondrial sort.

The reason for doing this is that mutations in mitochondrial DNA, like those in the nuclear genes, can cause disease. These diseases especially affect organs such as the brain and the muscles, which have high energy requirements. Each particular mitochondrial disease is rare. But there are lots of them. All told, there is about one chance in s,ooo that a child will develop such an inherited disease. That rate is similar, for example, to the rate of fragile-x syndrome, which is the second-most-common type of congenital learning difficulty after Down's syndrome. Mitochondrial disease is thus not a huge problem, but it is not negligible, either.

To find out whether mitochondrial transplantation could work in people (it has already been demonstrated in other species of mammal) Dr Mitalipov collected eggs from the ovaries of women with mutated mitochondria and others from donors with healthy mitochondria. He then removed the nuclei of both. Those from the healthy cells, he discarded. Those from the diseased cells, he transplanted into the healthy cells. He then fertilised the result with sperm and allowed the fertilised eggs to start dividing and thus begin taking the first steps on the journey that might ultimately lead to them becoming full-fledged human beings.

Nearly all of the experimental eggs survived the replacement of their nuclei, and three quarters were successfully fertilised. However, just over half of the resulting zygotes - as the balls of cells that form from a fertilised egg's early division are known - displayed abnormalities. That compared with an abnormality rate of just an eighth in control zygotes grown from untransplanted, healthy eggs.

This discrepancy surprised - and worried - Dr Mitalipov. The abnormality rate he observed was much higher than those seen when the procedure is carried out on other species. That, though, could be because this is the first time it has been attempted with human eggs. Each species has its quirks, and if mitochondrial transplants were to become routine, the quirks of humans would, no doubt, quickly become apparent. With tweaks, they could be fixed, Dr Mitalipov predicts.

However, turning this experiment into a medical procedure would be a long road, and not just scientifically. Dr Mitalipov has little doubt that his zygotes could be brought to term if they were transplanted into a woman's womb. That experiment, though, is illegal - and, in the view of some, rightly so. But the fact that it now looks possible will surely stimulate debate about whether the law should be changed. (From The Economist, October 27, 2012)