Signatures Of Human Migrations And Marriage Practices Where Chromosomes Agree, Found Bystanford Researchers

Signatures Of Human Migrations And Marriage Practices Where Chromosomes Agree, Found Bystanford Researchers

Examining shared stretches of genome from dozens of world populations, Stanford biologists have found a new way, not only to trace human history, but to help find hidden disease genes.

Stanford researchers have helped find a way to tease out the stretches of genome that are shared among affected individuals due to a recent common ancestor.

Your genome is a window onto your heritage – or, more precisely, several windows. There are the marks left by human evolution, the traces of ancient human migrations out of Africa and, scattered throughout, clues to your immediate ancestors' marriage habits.

This last detail is particularly interesting to medical geneticists. They're looking for the genes underlying rare, recessive diseases that mainly crop up in populations with a high number of marriages among close relatives, known as consanguineous marriages.

But this can be like looking for a needle in a haystack. Teasing out the stretches of genome that are shared among affected individuals due to a recent common ancestor, rather than from vestiges of deep population history, would significantly reduce the amount of hay.

A group of researchers, led by Stanford biology research associate Trevor Pemberton and biology Associate Professor Noah Rosenberg, has developed a way to attempt to do just that, laying bare worldwide genome patterns in the process.

The research paper, authored with Stanford biology Professor Marcus Feldman, Devin Absher and Richard Myers of the HudsonAlpha Institute for Biotechnology, and Jun Li of the University of Michigan, appeared Thursday in the American Journal of Human Genetics.

Chromosomal geography

Runs of homozygosity, or ROH, are segments of the genome where both chromosomes are identical. Homozygosity is what allows recessive traits, like blue eyes or cystic fibrosis, to appear at all – otherwise, the presence of a single dominant counterpart for a gene would mask the recessive characteristic.

Researchers have considered ROH before, but this comprehensive study of nearly 2,000 individuals from 64 populations across the world took a different approach. Using a new statistical model, the researchers "can disentangle ROH that are due to ancient population history from those that are due to recent consanguineous marriages," said Pemberton.

There are three flavors of ROH, separated by length. These all "follow different patterns," Pemberton explained, "which is what you'd expect when there are different processes underlying each of them."

Short- and middling-length ROH both vary with geography. Not only do they show distinct patterns on different continents, they increase in number as you move farther away from East Africa. It's a clear artifact of ancient waves of human migration.

"It's something novel, to see the signature of the distance from Africa in the ROH by separating them into classes of different size," Rosenberg said.

Africa, accordingly, also has the most diverse array of these short and intermediate ROH, while more recently populated regions such as Oceania and the Americas have the fewest.

These runs hearken back to events that are tens of thousands of years old. And many of the short runs – the more ancient of the two – appear to be fragments of even older ROH.

Gene hunting

The longest ROH, however, follow a different pattern. Younger and rarer, these runs don't obey a simple out-of-Africa progression. Instead, they appear most often in societies that have a history of marriage between relatives – in the Middle East and Central and South Asia, in particular. Adherence to the caste system in certain Indian towns, for instance, can severely limit spouse options.

These newer runs are also the ones that may help researchers narrow in on the chromosomal regions harboring the genes behind rare, recessive conditions –typically a side effect of relatively recent consanguineous marriage.

Researchers should be able to compare the ROH of an individual with a disease to those same chromosomal stretches in unaffected members of the same population group. "If it's frequently homozygous in the general population, you can largely discount the chromosomal region as a candidate," said Pemberton. "If it's rarely homozygous in the general population, it becomes a stronger candidate."

The group has already begun tentative collaborations with medical geneticists and has released a genomic map of the ROH locations.

"The idea is, the resource will be there and available for anyone who wants to come in and answer a question," Rosenberg said.

Marine genomes

Marine genomes

Craig Venter's team hits again with another large-scale sequence survey. This time they report on 197 complete prokaryotic genomes from the surface ocean's plankton. Note this means roughly a 15% increase in the total number of fully-sequenced species that was available this far. What is perhaps most notable, however, is that these species belong to a largely unexplored part of earth's microbial diversity: that living in the open ocean.

They divided the sequenced genomes into two sets: 34 that seem to be ubiquitous and abundant (present in most ocean samples), and 163 that appeared only at few locations, and compared their genome contents. Widespread planktonic species seem to have reduced genomes, with several functional classes such as gene regulation, cell motility, and membrane transport highly reduced or nearly absent. 

"cryptic escape"
In light of such differences, they propose that these ubiquitous species with reduced metabolic flexibility has adapted to survive in the open ocean by "becoming invisible", that is, reducing their size and metabolism to scape from predators and survive in a poor environment.

Altenative forces driving genome reduction
It is unclear whether reduced cell density can actually serve to scape predation from viruses or plankton-grazing organisms, and this hypothesis needs further testing. This first survey only looks at big numbers, and it is for certain that future more in-depth analyses may reveal more clues on what adaptative strategies are represented by these genomes. One interesting aspect is that forces driving genome reduction here should be different from those experienced by pathogens and endosymbionts, which constitute the best studied cases of genome reduction. In contrast to pathogens and endosymbionts, which live in rich and protected environments, marine prokaryotes thrive in one of the poorest environments with respect to nutrients. Therefore it would be very enlightening to look for differences and parallelisms in these two different adaptations that resulted in streamlined genomes.

Why only hungry K.lactis have sex?

Why only hungry K.lactis have sex?

One of my professors at the Univeristy of Valencia used to tell us that a Yeast's life was "mainly driven by food and sex", referring to the relevance and impact in this single-cell organisms of the signalling pathways in response to starvation, presence of nutrients or pheromones. One particular species of yeast, the diary yeast Kluyveromyces lactis, seemed to have combined both stimuli into a single pathway, requiring both starvation and pheromone signals to mate. Although this was known for decades, the specific mechanism and how it had evolved remained a mystery.


In a recent paper by the group of Alexander Johnson (UCSF), the origin of such phenotype has been established, by comparing regulation of mating genes in K. lactis, Saccharomyces cerevisiae, and Candida albicans. The evolutionary mechanism involved is that of a transcriptional rewiring, in which the core mating genes have been put under the control of the gene responsible for signalling starvation (RME1), which in turn is now also controlled by the mating factors (a/alpha). This intercalation of a new step within the mating signalling pathway effectively results in both stimuli being necessary for mating.

How could this happen? the implied scenario involves the acquisition of regulation by mating factors for RME1, at least four core mating genes loosing their reponsive elements to the mating factors - rather than change of the binding site of the factor, which was found to be similar to that in the other yeasts-, and the same genes acquiring responsive elements to RME1. 9 transitions in total. The first one (RME1 under control of mating) also occurs in S. cerevisiae, so it seems to have pre-dated the re-programming of the core mating genes control, effectively paving the way for the final rewiring. To unveil the order of the  other 8 transitions, one would need to find intermediate states in other yeasts. Given the potential deleterious effects of a mating gene loosing pheromone control, and the low probability of loosing one binding factor while acquiring the other one in four genes, I envision an intermediary state where the genes where responding to both RME1/mating factors. Then, the lost in a single core mating gene of the direct response to mating factors would render the pheromone-responsive elements in the other core genes non-functional (three of this core genes encode proteins that should be combined into a heterotrimer to function), thus leaving the only functional route that passing through RME1. Accumulating mutations would have then simply removed the pheromone-response site.

An interesting story of how regulation can effectively be altered by evolution in small steps.  Another important connection is that of the fact that for many fungi, most particularly pathogens such as Candida glabrata, we lack direct observation of the mating cycle although they conserve intact the mating genes and for some we have indirect evidence that they mate. Perhaps it all comes down to very specific requirements for mating, achieved by intercalating layers of regulation of mating genes as that found in K. lactis.

Risks of Genetic Engineering

Risks of Genetic Engineering
What are the risks of genetic engineering? The revolution that genetic engineering caused was profound. There was initially great concern about genetic engineering. The concerns centered on several aspects of this work. First, the bacteria used in these experiments were E. coli. This bacterium commonly lives on our intestines. People were worried about what will happen if this laboratory organism got out into our gut. Could the bacteria lead to cancer? This fear led almost to hysteria. Municipalities passed laws banning all genetic engineering work. A very famous scientist arrived to his laboratory one day to find the police out front, saying “you’ve broken our municipal ordinance against doing any gene swapping”. Doom scenarios were all over the place.

In 1975, a conference was held in California which brought together scientists, ethicists, physicians and lawyers to deal with this situation. This was a unique event in the history of science and government relations. The meeting was called by the scientists who were doing the work. They wanted some sort of feedback on what they were doing, because they were worried about the possible risks of genetic engineering.

At this meeting, after several days of heated discussions, they decided to do a moratorium on certain types of experiments. For example, until they knew what they were doing, they weren’t allowed to put cancer genes into bacteria to study them. They imposed extreme safety precautions on all of their types of experiments. Government agencies and institutional boards at research universities were set up to oversee this.

Scientists really asked for this oversight, which is very unusual, because scientists usually are of the type “just let us do our work and leave us alone, we would never harm you”. In this case, scientists were quite worried because this was so profound a change in biological manipulation.

In retrospect, these concerns were overblown, and no dangerous events have really occurred with genetic engineering. In fact, experiments that required severe precautions in 1975 are now done in high-school science labs. This doesn’t mean that we don’t need to constantly monitor this research. If we are dealing with harmful genes we must take extreme precautions.

Problems With Genetic Engineering

Problems With Genetic Engineering
There is public concern about the possible problems with genetic engineering. At the start of the 1970’s, these concerns were more widespread, as we didn’t know really what we were doing. When this technology was shown to be safe, these concerns abated. The possible risks of genetic engineering, however, have been a public concern, especially in Europe. These objections are threefold.

The first problem is that genetic manipulation is an unnatural manipulation of nature. This is what philosophers call the “yuck factor”. According to this people, eating food from a plant that has genes from bacteria is just “going too far”. There is just too much technology here.

There is no real response to this emotional argument. Scientists would say: “Well, all major crops have been genetically manipulated by humans even before genetic engineering was invented, so, that’s okay.”

Well, genetic engineering is really different. We’re taking genes from all over the plant, animal and bacterial world, and splicing them together. We can’t offer a rational response to this argument. We just can hope that these concerns will abate, as has happened with in vitro fertilization, for example.

The second of the supposed problems with genetic engineering is that genetically modified foods might be unsafe to eat. Some modifications of proteins, for example, may create a structure in the protein that some people might be allergic to. It turns out that most genetically modified plants grown today are not altered in the food part of the plant. They have some extra DNA sequences, but they are not modified in the food part. We’ve got to be careful with allergies, however.

The third of the risks is that genetically modified plants may be dangerous to the environment. Although a single gene is being transferred to a crop plant (one that makes it resistant to insects, for example), that gene might be transferred also to neighboring plants. This has been observed in some instances, but not in others. There is a danger of creation of super weeds with resistance. This is maybe a real risk, but not a really serious one.

There are two ways to look at these public concerns. One way is to proceed with caution, to do as many tests as we can, and make sure something doesn’t cause harm. The other way to look at it is the precautionary principle. This principle says “if you can’t prove that this would never cause a problem, don’t do it”. This argument has been common in Europe, but less so in other parts of the world. Certainly, this argument isn’t made in the less developed parts of the world, where genetic engineering has become a major way of improving plants.