Prenatal Whole Genome Sequencing: Just Because We Can, Should We?

ScienceDaily (Aug. 10, 2012) — With whole genome sequencing quickly becoming more affordable and accessible, we need to pay more attention to the massive amount of information it will deliver to parents — and the fact that we don’t yet understand what most of it means, concludes an article in theHastings Center Report. The authors are current or former scholars at the National Institutes of Health’s Department of Bioethics.

(Credit: www.babyphotos.co.in)


 

Most analyses of the ethical issues raised by whole genome sequencing have been “futuristic forecasting,” but the authors conclude that “this is problematic given the speed with which whole genome sequencing is likely to be incorporated into clinical care,” as its price falls to under $1,000.

Prenatal whole genome sequencing differs from current prenatal genetic testing practice in ethically relevant ways. Most notably, whole genome sequencing would radically increase the volume and scope of available prenatal genetic data. In contrast with current tests, which identify serious genetic conditions in fetuses at high risk of them, the new tests would likely be used by many more expectant parents and reveal a wide spectrum of genetic traits, including disease susceptibility.

Some of the ethical challenges posed by prenatal whole genome sequencing arise from the uncertainty of what the information means. The function of more than 90 percent of genes in the human genome is unknown and as a result, the article says, “much of the data generated from whole genome sequencing over the next few years (or even decades) will be of questionable utility.”

After analyzing the kind of information that whole genome prenatal testing will yield, the authors conclude that most of it would probably not be as helpful as information uncovered by the current categories of prenatal tests. They cited specific areas of concern.

First of all, the quality and quantity of information may augment parents’ anxiety. “To the extent that parents now think of their child as a ‘clean slate’ during pregnancy, the prenatal image of a normal, healthy baby will be dramatically altered by this technology,” the authors write. The anxiety over the results and changing views of what is “normal” could lead to an increase in pregnancy terminations.

Apart from reproductive decisions, the authors also foresee whole genome prenatal testing having a negative impact on child rearing. For example, if parents were able to get genetic information suggesting that their child’s predicted IQ may be low, they might not strongly encourage and support the child’s efforts in school.

Finally, the new technology could increase the tension between the interests of parents and children. Although parents have a strong interest in getting information that informs their reproductive choices, children have a competing interest in not knowing certain kinds of information about themselves — information that could limit their autonomy as they grow into adulthood.

Given the potential harms from prenatal whole genome sequencing, the authors make four preliminary recommendations.

  • Since only some of the information will be relevant to most parents’ reproductive decision-making, the medical community should make clear recommendations about which categories of information should be routinely offered to parents.
  • A child’s right “not to know” his or her genetic information should not be breached unless the information is clearly useful for the parents or can improve health outcomes in the child. “We recommend that the relevant societies revise their prenatal testing guidelines to ensure that their recommendations are sufficient and appropriate for the next generation of sequencing technologies.”
  • More data are needed to guide the deliberation of professional societies and the public.
  • Professional societies should play an active role in educating clinicians on how whole genome sequencing differs from traditional prenatal genetic tests, and on how to educate parents about the tradeoffs involved in choosing to engage in it.

The authors are Greer Donley, a law student at the University of Michigan School of Law and formerly a fellow in the Department of Bioethics at the National Institutes of Health; Sara Chandros Hull, a faculty member in the NIH Department of Bioethics who directs the National Human Genome Research Institute’s Bioethics Core at the National Institutes of Health; and Benjamin E. Berkman, a faculty member in the NIH Department of Bioethics with a joint appointment with the National Human Genome Research Institute.


Story Source:

The above story is reprinted from materials provided byThe Hastings Center.


Journal Reference:

  1. Greer Donley, Sara Chandros Hull, and Benjamin E. Berkman. Prenatal Whole Genome Sequencing: Just Because We Can, Should We? Hastings Center Report, 42, no. 4 (2012): 28-40 DOI: 10.1002/hast.50
Citation:

The Hastings Center (2012, August 10). Prenatal whole genome sequencing: Just because we can, should we?. ScienceDaily. Retrieved August 13, 2012, from http://www.sciencedaily.com/releases/2012/08/120810193757.htm
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Of Mice and Melodies: Research On Language Gene Seeks to Uncover the Origins of the Singing Mouse

ScienceDaily (Aug. 10, 2012) — Singing mice (scotinomys teguina) are not your average lab rats. Their fur is tawny brown instead of the common white albino strain; they hail from the tropical cloud forests in the mountains of Costa Rica; and, as their name hints, they use song to communicate.

A male singing mouse. (Credit: Photo courtesy of Bret Pasch)

University of Texas at Austin researcher Steven Phelps is examining these unconventional rodents to gain insights into the genes that contribute to the unique singing behavior — information that could help scientists understand and identify genes that affect language in humans.

“We can choose any number of traits to study but we try and choose traits that are not only interesting for their own sake but also have some biomedical relevance,” said Phelps. “We take advantage of the unique property of the species.”

The song of the singing mouse song is a rapid-fire string of high-pitched chirps called trills used mostly used by males in dominance displays and to attract mates. Up to 20 chirps are squeaked out per second, sounding similar to birdsong to untrained ears. But unlike birds, the mice generally stick to a song made up of only a single note.

“They sound kind of soft to human ears, but if you slow them down by about three-fold they are pretty dramatic,” said Phelps.

Most rodents make vocalizations at a frequency much too high for humans to hear. But other rodents typically don’t vocalize to the extent of singing mice, which use the song to communicate over large distances in the wild, said Andreas George, a graduate student working in Phelps’ lab.

Within the last year Phelps research on the behavior of the mouse has appeared in the journals Hormones and Behaviorand Animal Behavior. But one of his newest research projects is looking deeper: examining the genetic components that influence song expression. Center stage is a special gene called FOXP2.

“FOXP2 is famous because it’s the only gene that’s been implicated in human speech disorders specifically,” said Phelps.

Having at least one mutated copy of the gene has been associated with a host of language problems in humans, from difficulty understanding grammar to an inability to make the precise mouth movements needed to speak a clear sentence.

The FOXP2 gene is remarkably similar overall between singing mice, lab mice and humans, said Phelps. To find parts of the gene that may contribute to the singing mouse’s songs, Phelps is searching for sequences unique to the singing mouse and testing them for evidence of natural selection, which weeds out mutations with no likely observable effect from those that are likely to contribute to singing behavior.

“Those two things go a long way,” said Phelps, ” And when you look at the intersection of those two things they give us a really good set of candidate regions for what might be causing species differences.”

The Molecular Connection

Most genetic mutations don’t cause serious problems. They are often a part of the genome that is not expressed, still make a functional product, or are simply drowned out by the amount of genes and gene products that are working correctly.

FOXP2 mutations, on the other hand, can have significant effects on speech because of the gene’s role as a transcription factor — a gene product that helps control the expression of other genes.

This means a mutation in the FOXP2 gene can start a chain of events that can lead to reduced expression, or possibly even no expression, of a number of other genes.

Phelps and his team are figuring out what activates FOXP2 expression and the genes that are expressed after its activation by playing singing mice recording of songs from their own species and neighboring species and observing the gene expression patterns.

“We found that when an animal hears a song from the same species, these neurons that carry FOXP2 become activated. So we think that FOXP2 may play a role in integrating that information,” said Lauren O’Connell, a post-doctoral researcher in the Phelps lab.

Learning what activates FOXP2 and what genes are activated by it could provide clues into how outside stimuli affects gene expression and what genes are important in the understanding and integration of information, said Phelps.

“We ask two things, whether there are sequence changes in the DNA that are associated with the elaboration of the song and whether particular elements seem to be interacting with FOXP2 more,” said Phelps. “That gives us leads into what role FOXP2 might play into the elaboration of vocalization.”

Big Data Mining

Phelps’ uses next-generation sequencing to decipher how FOXP2 interacts with DNA to regulate the function of other genes. The process involves reading tiny fragments of overlapping DNA so that the entire sequence can be deduced. It is a procedure that generates massive amount of data that only the processing power of a supercomputer can handle, said O’Connell.

“You need TACC to do it,” said O’Connell, referring to the Texas Advanced Computing Center, which houses the supercomputers the lab uses. “The more data you have, the more memory it requires, so a lot of the data we can only process on Lonestar’s high memory nodes.”

Lonestar and Ranger are the names of the two supercomputers that the Phelps lab uses to crunch their data, with Ranger running programs in two hours that used to take the lab three days to run on their desktop. Both computers are among the top 100 supercomputers in the world.

Future Applications

At the most basic level, Phelps’ research is asking questions about the biology and behavior of an exotic rodent. But finding out more about the link between FOXP2 and the song of the signing mouse could bring a better understanding into how the gene may contribute to language deficits in people, especially those with autism, said Phelps.

“When people do genome wide association studies in humans the genetic variation tends to occur in huge blocks. So if you get some DNA sequence that predicts a phenotype, like risk for autism, it’s very hard to know what aspect in this very long stretch of DNA is actually important for that,” said Phelps.

By identifying the sequences of DNA that interact with FOXP2 and other associated genes that are most vital to gene function, researchers in the future might be able to narrow down the “huge blocks” where a possible causal sequence is located into smaller pieces. In other words, reducing the size of the metaphorical haystack to a size where finding the needle is a much simpler task.

While a singing mouse may seem like a strange place to look to study the impact of genetics on language, O’Connell says that the advent of gene sequencing technology is allowing a whole menagerie of animals to be used for research that could later be applied to humans.

“I use TACC to sequence a lot of different animals: birds and fish and frogs and mammals and beetles,” said O’Connell, mentioning the other organisms she studies outside of the Phelps lab. “Each of these model systems has something unique to contribute that teaches us about biology that is still applicable to humans.”

Story Source:

The above story is reprinted from materials provided byUniversity of Texas at Austin, Texas Advanced Computing Center. The original article was written by Monica Kortsha.


Journal References:

  1. Bret Pasch, Andreas S. George, Heather J. Hamlin, Louis J. Guillette, Steven M. Phelps. Androgens modulate song effort and aggression in Neotropical singing miceHormones and Behavior, 2011; 59 (1): 90 DOI:10.1016/j.yhbeh.2010.10.011
  2. Bret Pasch, Andreas S. George, Polly Campbell, Steven M. Phelps. Androgen-dependent male vocal performance influences female preference in Neotropical singing miceAnimal Behaviour, 2011; 82 (2): 177 DOI: 10.1016/j.anbehav.2011.04.018
Citation:

University of Texas at Austin, Texas Advanced Computing Center (2012, August 10). Of mice and melodies: Research on language gene seeks to uncover the origins of the singing mouse. ScienceDaily. Retrieved August 13, 2012, from http://www.sciencedaily.com/releases/2012/08/120810193755.htm

Study of Fruit Fly Chromosomes Improves Understanding of Evolution and Fertility

ScienceDaily (Aug. 10, 2012) — The propagation of every animal on the planet is the result of sexual activity between males and females of a given species. But how did things get this way? Why two sexes instead of one? Why are sperm necessary for reproduction and how did they evolve?

(Credit: http://leavingbio.net/)


 

These as-yet-unresolved issues fascinate Timothy Karr, a developmental geneticist and evolutionary biologist at Arizona State University’s Biodesign Institute. To probe them, he uses a common fruit fly, Drosophilamelanogaster — an organism that has provided science with an enormous treasure-trove of genetic information.

“My research focuses on the evolution of sex and in gamete function,” Karr says. “I focus primarily on the sperm side of the sexual equation. I’m interested in how they originated and how they are maintained in populations.”

Karr’s current study, in collaboration with researchers at the University of Chicago, recently appeared in the journal BMC Biology. The study reexamines an earlier paper that analyzed the sex chromosomes of fruit flies during spermatogenesis — the process that produces mature sperm from germ cells.

While the previous paper, by Lyudmila M Mikhaylova and Dmitry I Nurminsky, argued against the silencing of sex-linked genes on the X chromosome inDrosophila during meiosis — a process referred to as Meiotic Sex Chromosome Inactivation (MSCI) — the reanalysis presented by Karr suggests MSCI is indeed occurring.

The work sheds new light on the evolution of sperm structure and function, through an analysis of Drosophila genes and gene products. As Karr explains, the research has important implications for humans as well: “The more direct, biomedical aspect is that when we learn about the function of a gene that encodes a protein in Drosophila sperm, we can immediately see if there’s a relationship between these genes and their functions and known problems with fertility in humans.”

Super Fly

Perhaps no other model organism has yielded more insights into human genetics than the tiny fruit fly Drosophilamelanogaster. In 1906, Thomas Hunt Morgan of Columbia University began work on D. melanogaster, (one of over 1500 species contained in the Drosophila genus) capitalizing on the species’ ease of breeding, rapid generation time and ability to readily produce genetic mutants for study. Morgan’s efforts with Drosophila led to the identification of chromosomes as the vector of inheritance for genes, and earned him the 1933 Nobel Prize in Medicine.

Drosophila are yellow-brown in color, have reddish eyes and transverse black rings across their abdomen. Females are about 2.5 millimeters long, while males are slightly smaller and may be easily identified by their darker color.

Most importantly, the similarity in the genetic systems of fruit flies and other eukaryotic organisms including humans makes these model organisms extremely useful analogues for the study of common genetic processes including transcription and translation.

Roughly 75 percent of known human disease genes have recognizable correlates in the fruit fly genome and 50 percent of fly protein sequences have mammalian homologs. (The complete genome of D. melanogaster was completed in 2000.)

Chromosomes: genetic storehouses

Humans have 23 pairs of chromosomes, or 46 chromosomes in all. Of these, 44 are known as autosomes and consist of matched pairs of chromosomes, known as homologous chromosomes. Each homologous chromosome contains the same set of genes in the same locations along the chromosome, though they may appear in differing alleles, which can affect the passing of genetic traits.

The current study however, focuses not on the autosomes but on the remaining pair of chromosomes, known as sex chromosomes. Females contain two X chromosomes, which are homologous, as in the case of the autosomes. By contrast, males are identified as having one X chromosome and one (much smaller) Y chromosome.

While drosophila only have a total of 4 chromosomes, they too display sexual dimorphism, with females carrying the double X chromosomes and males carrying XY. The two X chromosomes in female fruit flies, as in mammals, make them a homozygous sex as compared with the XY condition in males, known as heterozygous.

“There are certain aspects to the composition of these sex chromosomes that have intrigued evolutionary biologists for a long time,” Karr notes. One such issue involves an apparent reduction in the number or the level of expression of sex-linked genes on the X chromosome during spermatogenesis. It is believed that this reduction or silencing of genes on the X chromosome may have profound implications for the evolution of sex chromosomes.

During meiotic development of a sperm cell, nature attempts to compensate for the fact that females have two X chromosomes and therefore enjoy a numbers advantage in terms of genes, compared with males. To overcome the bias for female X-linked genes, the X chromosome undergoes inactivation during meiotic sexual differentiation of male gametes, resulting in an underrepresentation of sex-specific genes on the X chromosome. Some of these genes, which may be beneficial to males, are moved from the X chromosome, to the autosomes, where they may be expressed.

The relocation of male-biased genes to the autosomes may be due to a selective advantage favoring genes that move off the X chromosome and therefore avoid X-inactivation during meiosis. Such theories remain controversial however, as statistical analyses are used to evaluate gene frequencies and expression levels, making the proper categorization of genes particularly challenging. “The data we create and generate to support our ideas and hypotheses are messy, there’s noise in them,” Karr says. “Such noise is inherent in the history of evolution.”

In addition to the steady stream of insights into chromosome evolution, Drosophila are being used as a genetic model for a variety of human diseases including Alzheimer’s, neurodegenerative disorders, Parkinson’s, Huntington’s, as well as extending knowledge of the underlying mechanisms involved in aging, oxidative stress, immunity, diabetes, and cancer.

Story Source:

The above story is reprinted from materials provided byArizona State University. The original article was written by Richard Harth.


Journal Reference:

  1. Maria D Vibranovski, Yong E Zhang, Claus Kemkemer, Hedibert F Lopes, Timothy L Karr, Manyuan Long. Re-analysis of the larval testis data on meiotic sex chromosome inactivation revealed evidence for tissue-specific gene expression related to the drosophila X chromosomeBMC Biology, 2012; 10 (1): 49 DOI:10.1186/1741-7007-10-49

Citation:

Arizona State University (2012, August 10). Study of fruit fly chromosomes improves understanding of evolution and fertility.ScienceDaily. Retrieved August 12, 2012, from http://www.sciencedaily.com/releases/2012/08/120810144715.htm