P53 and skin pigmentation

Since we just mentioned skin coloration (here, in passing), and we have previously discussed how the p53 protein is involved with it (here), it's interesting that there is now more news on the subject.

Protein Linked To Bone Marrow Failure In Humans Found Through Study Of Dark-skinned Mice (7/20/08)

McGowan, Barsh, and their colleagues found that skin from the feet of the mutant mice exhibited elevated levels of p53. This elevation, or "activation," of p53 stimulated the production of a protein called Kit ligand that stimulates the growth of pigment cells, which turned the mice's skin darker than normal. In contrast, mutant mice unable to express p53 had normal levels of Kit ligand. They also had light-colored feet and unaffected numbers of red blood cells. ...

The researchers hypothesize that increased activation of p53 affects different types of cells in the body in different ways. In skin cells, it increases the amount of Kit ligand and causes darker skin, whereas in bone marrow cells it causes anemia by causing the death of red blood cell precursors.

Is there some lesson in this? Well, p53 is generally regarded as a "good" protein, because it helps ward off cancer that would otherwise result from DNA damage. But it does this by promoting apoptosis of cells affected by the DNA mutation. Anemia is the result when too many red blood cells die.

And the skin darkening? Earlier studies indicate that is also a side effect of increased levels of p53. Such unexpected – and not always desirable – side effects are the reason that developing drugs to treat disease is so difficult. There is so much unexpected interconnection of our cellular machinery, adjusting something in one place can lead to problems in quite different places.

Tags: p53

Blue eyes

The question of eye color seems to interest quite a few people. Previous discussions (here, here) have been among the most popular.

The actual genetics behind eye color remained somewhat obscure until February of this year. Although it's no longer new news, the findings are worth mentioning.

Humans certainly aren't the only animals having variable eye color. But the surprising thing is that (according to the primary author of the new research), until just a few thousand years ago, blue-eyed humans would have been very rare, at best.

Blue-eyed Humans Have A Single, Common Ancestor (1/30/08)

New research shows that people with blue eyes have a single, common ancestor. A team at the University of Copenhagen have tracked down a genetic mutation which took place 6-10,000 years ago and is the cause of the eye colour of all blue-eyed humans alive on the planet today.

“Originally, we all had brown eyes”, said Professor Eiberg from the Department of Cellular and Molecular Medicine. “But a genetic mutation affecting the OCA2 gene in our chromosomes resulted in the creation of a “switch”, which literally “turned off” the ability to produce brown eyes”. The OCA2 gene codes for the so-called P protein, which is involved in the production of melanin, the pigment that gives colour to our hair, eyes and skin. The “switch”, which is located in the gene adjacent to OCA2 does not, however, turn off the gene entirely, but rather limits its action to reducing the production of melanin in the iris – effectively “diluting” brown eyes to blue.

Note what this is saying. It is melanin that produces brown eyes, and melanin production is controlled by the OCA2 gene. A person in whom melanin isn't produced because both copies of OCA2 are faulty will not only not have brown eyes, but will not have brown color anywhere in the skin. However, if there is a certain mutation in both copies of a gene (known as HERC2) adjacent to OCA2 – not in OCA2 itself, as some accounts incorrectly state – production of melanin due to OCA2 will be reduced enough to produce blue eyes, while in skin there is still enough melanin produced to allow some brown coloration.

The reasoning that all people who now have blue eyes descended from a single individual who lived 6-10,000 years ago is based on different evidence, but it's a little more speculative. Another account outlines the argument:

Don't It Make Your Brown Eyes Blue? (2/1/08)

[B]y comparing people with brown or blue eyes, including people from Jordan and Turkey, the researchers were able to pinpoint the exact mutation. It wasn't on the OCA gene but rather on a nearby gene called HERC2. ...

Because blue eye color is found almost exclusively in people of European descent, Eiberg's team speculates that the mutation traces back to the Neolithic expansion, when people in the Black Sea region migrated to northern Europe 6000 to 10,000 years ago.

Two other studies, both appearing in this month's issue of The American Journal of Human Genetics, examined blue eyes in different populations and found the same mutation. The researchers also suggested a common ancestor for all blue-eyed individuals. These teams, however, did not estimate an age for the mutation. Geneticist Richard Sturm of the University of Queensland in Brisbane, Australia, an author of one of the papers says that someday scientists may find additional mutations that cause blue eyes but for now, the signs point to a single change.

Further reading:

One Common Ancestor Behind Blue Eyes – 1/31/08 article at LiveScience

The Family Tree of Blue-Eyed Individuals (2/6/08) – blog article that gives a bit more of the genetic details

Blue eyed people have a single, common ancestor (2/3/08) – another article, which gets some of the details wrong

Tags: eye color, blue eyes

Our plant relatives

Humans aren't related merely to other animals – plants are kinfolk too. In fact, we share some genes with ancestors of both animals and plants, genes not found even in most modern plants.

Green Algae: The Nexus Of Plant-Animal Ancestry

Genes of a tiny, single-celled green alga called Chlamydomonas reinhardtii may contain scores more data about the common ancestry of plants and animals than the richest paleontological dig. This work is described in an article in Science.

A group of researchers, including Arthur Grossman of the Carnegie Institution, report on the results of a major effort to obtain the full library of genes, or the genome sequence, of Chamydomonas and to compare its ~15,000 genes to those of plants and animals, including humans. The research shows that this alga has maintained many genes that were lost during the evolution of land plants, has others that are associated with functions in humans, and has numerous genes of unknown function, but which are associated with critical metabolic processes.

In particular, cilia are important structures of some eukaryotic cells, are inherited from the common ancestor of plants and animals. Cilia are found in animal cells, analogous to flagella in Chamydomonas, but have no analogue in most plant cells.

Chlamydomonas, affectionately called Chlamy, is an alga of 10 micrometres in size that is present in soil and freshwater environments. It performs photosynthesis like plants, but it diverged evolutionarily from flowering land plants about 1 billion years ago. It is even more distantly related to animals (the split between animals and plants was ~1.6 billion years ago). Chlamy moves using two anterior, hair-like flagella that were lost by its cousins, the flowering land plants, after the evolutionary split of the two lineages. The flagella are equivalent to the cilia and centrioles in animal cells. Centrioles are structures involved in cell division; they form a spindle apparatus, which helps separate genetic material into two new cells during mitosis. Cilia are important to many animal functions.

More information:

The Chlamydomonas Genome Reveals the Evolution of Key Animal and Plant Functions (Sub. rqd.)

Study involving more than 100 scientists provides new insights on green algae

Scientists Sequence Genome of Soil-Dwelling Green Alga

Tags: Chlamydomonas, cilia

Disease genes

This is old news (over a month), and it was widely reported in the general media, so I'm sure most readers are aware of it. But it seems important enough to note here, just for the record. It might be considered one of the most important science stories of the year.

Largest Ever Study Of Genetics Of Common Diseases Published

The Wellcome Trust Case Control Consortium, the largest ever study of the genetics behind common diseases such as diabetes, rheumatoid arthritis and coronary heart disease, published its results in the journals Nature and Nature Genetics.

The £9 million study is one of the UK's largest and most successful academic collaborations to date. It has examined DNA samples from 17,000 people across the UK, bringing together 50 leading research groups and 200 scientists in the field of human genetics from dozens of UK institutions. Over two years, they have analysed almost 10 billion pieces of genetic information.

Information about a couple of autoimmune diseases figured prominently in the results.

Amongst the most significant new findings are four chromosome regions containing genes that can predispose to type 1 diabetes and three new genes for Crohn's disease (a type of inflammatory bowel disease). For the first time, the researchers have found a gene linking these two autoimmune diseases, known as PTPN2.

The study has also confirmed the importance of a process known as autophagy in the development of Crohn's disease. Autophagy, or "self eating", is responsible for clearing unwanted material, such as bacteria, from within cells. The may be key to the interaction of gut bacteria in health and in inflammatory bowel disease and could have clinical significance in the future.

"The link between type 1 diabetes and Crohn's disease is one of the most exciting findings to come out of the Consortium," says Professor John Todd from the University of Cambridge, who led the study into type 1 diabetes. "It is a promising avenue for us to understand how the two diseases occur. The pathways that lead to Crohn's disease are increasingly well understood and we hope that progress in treating Crohn's disease may give us clues on how to treat type 1 diabetes in the future."

There were also findings about genetic factors in obesity, type 2 diabetes, and heart disease. In fact, seven major disease in all:

These are bipolar disorder, Crohn's disease, coronary heart disease, hypertension, rheumatoid arthritis and type 1 and type 2 diabetes.

Interestingly, rheumatoid arthritis is also an autoimmune disease. And the immune system (especially in regard to inflammation) probably plays some role in other ailments on this list.

Most readers here probably understand that very seldom is a single gene ever the sole "cause" of a particular disease. Instead, what has been found, in this study and in others, is a number of variants (called alleles) of a variety of genes, where one of more of the variants, if present in an individual, increases the person's risk of eventually developing the disease – conditioned on the presence of other genetic variations, environmental conditions, and so forth. As another account explains:

Sick Genes

[G]enes, although potent predictors, are not always the sole cause of particular diseases. For instance, environmental factors, lifestyle (diet, exercise, etcetera) and exposure to infections can all play roles in determining whether an individual will develop heart disease, for example. "It's about hundreds of genes in your genome contributing a threshold of genetic susceptibility," Todd says. "It's not about one gene."

Nevertheless, on average, having one copy of some of the newly identified genes raises a person's chances of developing one of the seven studied diseases by 20 to 40 percent, and those with two copies face nearly double that risk, researchers say. "What hasn't been clear is exactly which bits of the genome have an effect and which variants make people more [or less] likely to get a disease," Donnelly notes.

Additional news reports: here, here, here, here.

Tags: genetics, disease genes