Blue babies and mutant flies

My brother was born blue.

He wasn’t cold, and he didn’t have silver toxicity, or any of the multidues of diseases that can cause blue skin. The umbilical cord had gotten wrapped around his neck, cutting off circulation. It was 1976, the days before routine fetal monitoring, and for a while, it wasn’t clear if my brother was going to live. After several weeks in the ICU, my brother did survive, and the only scar of his traumatic birth is a mild hearing impairment.

The minutes without oxygen–no one knows exactly how long the cord was wrapped around my brother’s neck–killed brain cells crucial in hearing high-pitched noises. This lack of oxygen, known as hypoxia, is toxic to all kinds of cells, not just neurons. Although most people can get all the oxygen they need in everyday life, just a few minutes without oxygen can be deadly.

Almost all cellular processes requires oxygen. You need oxygen to create energy from food in the form of ATP. If the cell doesn’t have ATP, it’s like a car without fuel. And just as an empty tank means a dead car, the lack of ATP means a dead cell. Except for some microbes, all organisms need oxygen. The question is: how much? Can some organisms be manipulated to be immune to the harmful effects of hypoxia?

<i>Drosophila melanogaster</i>

Gabriel Haddad and colleagues at the University of California, San Diego created a strain of hypoxia-tolerant flies. Using the well-studied fruit fly Drosophila melanogaster, Haddad gradually exposed each new generation of flies to ever lower levels of oxygen. Their results were published online today in the journal PNAS¹. After more than 200 generations, Haddad’s flies could survive in air with only 4% oxygen. Normal air has around 21% oxygen, and prolonged exposure to levels below 19% oxygen can cause problems.

By comparing the genes that were active in the hypoxia-tolerant flies to the genes in flies not exposed to the low oxygen levels, the scientists could tell how the flies adapted to the environment. Haddad’s group found the genetic changes happened in two regions of the fly’s genome. Over 80% of the genes were located on the X Chromosome, in a region that is also home to a receptor gene known as Notch. This receptor transmits signals from chemicals on the outside of the cell to the inside of the cell.

Flies that had been bred to withstand low levels of oxygen, had much higher levels of Notch genes turned on than control flies. And hypoxia-tolerant flies without a functioning Notch gene died at much higher oxygen levels than hypoxia-tolerant flies with an intact Notch gene (6% vs. 4%). Although Haddad’s team isn’t sure exactly why Notch helps Drosophila survive hypoxia, other scientists have found evidence that increased levels of the Notch receptor helps protect cells from hypoxia in both mice² and humans³.

The authors hope that understanding how Notch helps organisms survive low oxygen levels will lead to treatments for hypoxia. No massive infusion of Notch would have helped my brother–you can’t (yet) resurrect dead neurons. But maybe one day other blue babies or heart attack and stroke victims will be able to prevent the cell death that comes from hypoxia.

References:
1. Zhou D, et al. (2011) Experimental selection of hypoxia-tolerant Drosophila melanogaster. Proc Natl Acad Sci. Link.
2. Fan C, et al. (2005) Gene expression and phenotypic characterization of mouse heart after chronic constant or intermittent hypoxia. Physiol Genomics 22:292–307. Link.
3. Bedogni B, Warneke JA, Nickoloff BJ, Giaccia AJ, Powell MB (2008) Notch1 is an effector of Akt and hypoxia in melanoma development. J Clin Invest 118:3660–3670. Link.

Sharing is caring…in bacterial metabolic networks

Bacteria live pretty much everywhere, dividing happily in places from stomach acid to deep-sea vents. Bacteria and Archaea can live in so many different places because their genomes are incredibly flexible–they can alter, lose and duplicate genes almost at will.  Although scientists knew that prokaryotes could acquire genes from their neighbors (it’s a known contributor to antibiotic resistance), this method of gaining new DNA was thought to be very rare and only occur under strong pressures in the environment, like deadly antibiotics.

The idea that bacteria could share their genes, known as horizontal gene transfer, was first discovered by Japanese microbiologists in 1959¹ in a study of antibiotic resistance in different species of bacteria. They found that bacteria could acquire entire genes from other bacteria–even other species of bacteria. Since then, evolutionary biologists have been trying to figure out how important this feature is to both bacteria and the evolution of life on earth.

One way to study this is to look at similarities and differences in bacterial genes in different species. Biologist Linda Fothergill-Gilmore wrote in a review paper² that the first bacterial genome was likely small and simple. As time passed, genes got duplicated and mutated, ultimately giving rise to the complicated synthesis and breakdown of sugars, proteins, nucleic acids, and fats that we see today. Eukaryotes are only known to use this method of gene duplication and mutation as fodder for evolution. But the 1959 Japanese study, followed by thousands of paper on horizontal gene transfer, hinted that bacteria had another way of acquiring new genes. If a bacterial gene evolved in the “standard” eukaryotic way–by duplicating and mutating over time–the new gene’s function would be obviously related to other genes in the bacterium. If, on the other hand, a bacterium got a new gene by swallowing an entire gene from its neighbor (lending new meaning to the phrase “Big Gulp”), and then pass that gene along to its daughter cells (known as vertical gene transfer), that swallowed gene wouldn’t have any close links to its host genome.

In a paper published yesterday in BMC Evolutionary Biology, a team led by Sebastian Bernhardsson of the Niels Bohr Institute created a network to show how different genes were shared amongst 134 different species of bacteria³. Bernhardsson’s team called each gene a “node” and noted how many different bacterial species shared this gene. The bigger the node (pictured as a circle), the more bacterial species that shared this gene. Their results looked like this (Figure 1):

Not surprisingly, they found a large core of basic enzymes that performed common duties in many different bacteria. Most of these genes appeared to arise in the “eukaryotic” way, by a gene getting duplicated and then mutating and doing something new. These genes were more likely to have close evolutionary links to nearby genes, which indicates that the two genes originated from the same source. At the periphery of the network, where genes were shared among relatively few bacterial species, Bernhardsson and colleagues found that bacteria were more likely to have acquired these genes through horizontal gene transfer. Obtaining a more peripheral gene may not sound like a big deal, but it likely gave the bacteria radically new functionality. And new functionality means the bacteria can live in a new environment and evolve further.

This result, the authors write, “lends additional support to the importance of horizontal gene transfer during bacterial metabolic evolution where new reactions are attached at the periphery of the network.”

Whereas horizontal gene transfer may not have had a significant effect early in the evolution of metabolism, it has allowed bacteria to expand their abilities into new areas later in the history of life.

This pup summarizes the results thusly:

References:

1. Ochiai K, Yamanaka T, Kimura K, Sawada, O (1959). “Inheritance of drug resistance (and its transfer) between Shigella strains and Between Shigella and E. coli strains” (in Japanese). Hihon Iji Shimpor 1861: 34
2. Fothergill-Gilmore LA (1986). “The evolution of the glycolytic pathway.” Trends in Biochemical Sciences 11:47-51. doi:10.1016/0968-0004(86)90233-1
3. Bernhardsson S, Gerlee P, Linzana L (2011). “Structural correlations in bacterial metabolic networks.” BMC Evolutionary Biology. doi:10.1186/1471-2148-11-20

Friends are the family you choose

At your next family gathering, take a look around. Although you might not want to admit it, you can often see genetic similarities between your relatives. It might be as obvious as inheriting your grandfather’s propensity towards male pattern baldness, or as subtle as also inheriting his enjoyment of a good Scotch. Like it or not, however, your family is your family and there’s not a damn thing you can do about it.

Friends are different.  You can pick and choose your friends, and you can do your best to avoid the genetic foibles you and your family are stuck with.

But a new study published today in PNAS shows that your friends are also likely to share your genetics. The study, led by James Fowler and Nicholas Christakis, found that people with certain gene variants were more likely to have friends with that variant. The reverse was also true: people without the allele were more likely to have friends without that allele.

It’s interesting, but previous studies have shown that when it comes to friends, “birds of a feather flock together.” That is, people tend to befriend others who are like them. Barflies and boy band fans tend to come in packs. But there isn’t a “barfly” or “boy band” gene, so researchers didn’t know whether these behavioral tendencies also tracked on the genetic level.

Fowler and Christakis used data from the the National Longitudinal Study on Adolescent Health and the Framingham Heart Study Social Network. Each of these studies asked participants to name several friends, and obtained genetic data from all of the people involved. From this data, the researchers could look at the relationships between friendship, genotype (which of the gene variants the person had), and phenotype (how the friends behaved).

The authors used two well-researched genes to categorize the study participants. One gene, known as DRD2, is a receptor for dopamine, a neurotransmitter that  works in the brain’s reward system. DRD2 has two major variants, one of which is linked to an increased risk for alcoholism. A 2007 study in Drugs and Chemical Toxicology found that some variants of CYP2A6 were associated with openness to new experience. People who score high in openness show a higher appreciation of art and music, have more vivid imaginations, and are more likely to think critically about issues of politics and religion. 

Ultimately, the authors found that a person’s friends were much more likely to have the same DRD2 and CYP2A6 variants. Write Fowler and Christakis:

People’s friends may not only have similar traits, but actually resemble each other on a genotypic level, even at the level of specific alleles and nucleotides.

The authors say that these results change what scientists think about how the genetics of a population is structured. Before, scientists believed that long-term partnerships and reproduction were the main things that affected which genes a group of people had. These results, however, show that friendship also plays a role.

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