Dr. James Noonan

Gene Regulation and Human Evolution

Prabhakar S, et. al, and Noonan JP. 2008. Human-specific gain of function in a developmental enhancer. Science. 321(5894):1346-50.

Wray GA, Babbitt CC. 2008. Genetics. Enhancing gene regulation. Science. 321(5894):1300-1.

Duret L, Galtier N. 2009. Comment on “Human-specific gain of function in a developmental enhancer”. Science. 323(5915):714; author reply 714.

Sholtis SJ, Noonan JP. 2010. Gene regulation and the origins of human biological uniqueness. Trends Genet. 26(3):110-8.

Question 1

Can you briefly tell us a bit about yourself, your career path over the years, and specifically what brought you to begin working on evolution and development and specifically human evolution?

Michael J. F. Barresi

Question 2

Can you briefly tell us a bit about yourself, your career path over the years, and specifically what brought you to begin working on evolution and development and specifically human evolution?

Michael J. F. Barresi

Question 3

I read that out of 110,000 gene enhancer sequences identified in the human genome, HACNS1 has undergone the most change throughout evolution. Can you elaborate on this finding and discuss what makes this enhancer prone to mutations, specifically what created this hot spot for gene conversion and induce a faster rate of biased gene conversions?

Carla Velez (and Wenxin Cai)

Question 4

After the 13 clustered human-specific substitutions were identified, I noticed that you chose the two independent groups of 3 substitutions and 6 substitutions located on the two ends of the 81 bp genomic region. Is there a reason for that? Why skip the three substitutions in the middle of the 81 bp region? It seems that those three substitution sites are also part of many predicted transcription factor binding sites.

Yisi Lu

Question 5

Do you plan on, now that you have your own lab, going back to the other ones?

Michael J.F. Barresi

Question 6

You point out that there is no known regulatory code analogous to the genetic code, which makes it difficult to distinguish between nucleotide substitutions that are neutral events or that alter regulatory activity. But have you or others in this research field noticed any particular groups of nucleotide substitution events that follow a particular pattern of gene regulation? (which would suggest that the putative regulatory code comprises several ‘sub codes’.

Yvanka De Soysa

Question 7

The mouse embryos with the human construct have very reproducible HACNS1 expression patterns, but the embryos with either the rhesus or chimp orthologs vary much more in where HACNS1 is expressed (particularly the chimp embryos in Fig. 1 and the 2nd rhesus embryo in Fig. 2a). Is this simply a byproduct of using murine embryos, or might something else be contributing to it? Additionally, what do you expect happens to HACNS1 expression in developmental stages later than 13.5?

Danielle Vazquez

Question 8

There is a figure showing that the reporter gene is expressed in distal anterior forelimb of HACNS1 transgenic mouse. In chimpanzee and rhesus, orthologs fail to drive reporter gene expression in the distal limb bud so they don’t have opposable thumbs as human. Could this expression pattern also be established or enhanced by other players opposing the enhancer activity of HACNS1, such as Hox genes?

Wenxin Cai

Question 9

In your test statistic, you use the sequence of seven other terrestrial vertebrates to determine the log-likelihood of observing the human sequence, how were these vertebrates chosen?

Julie Wang

Question 10

Duret & Galtier (2009) suggest that the evolution of this 81- bp region is explained by BGC due to the spatiotemporal distribution of recombination hotspots in humans. This criticism also claims that “the strong functional shift in human HACNS1 enhancer activity probably results from the accumulation of numerous weakly deleterious substitutions,” meaning that these functional changes may not have to do with adaptation. Were these suggestions considered previously in your lab? If so, how did you eliminate them as explanations for results? If they weren’t considered previously, how are you now interpreting your results and how will you proceed?

Samantha Torquato

Question 11

We did a little further research and found your response to the comment paper by Duret and Galtier. Was there ever any more correspondence formally or informally regarding your response? Have you done any further research on the topic that sheds more light on the BGC hypothesis vs the positive pressure argument?

Rachael Stein

Question 12

You stated that “Multiple lines of evidence suggest that the functional changes in HACNS1 are due to adaptive evolution.” Please explain the link between environmental demands and the gene itself. In other words, how exactly is the environment regulating the HACNS1?

Caterina Lagdameo

Question 13

At the conclusion of the paper, it is said that GBX2 and CENTG2 are thought to be involved with HACNS1 and more research on its localization during development must be done. Why were these two genes hypothesized to be involved and how are they thought to function?

Sarah Izen

Question 14

Currently in your opinion what are the most pressing questions in the study of human evolution, and what steps is your lab taking to address these questions?

Michael J.F. Barresi