New Insights Into The Evolution Of The Human Genome

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New Insights Into The Evolution Of The Human Genome

http://www.medicalnewstoday.com/articles/85000.php

Which came first, the chicken genome or the egg genome?

Researchers have answered a similarly vexing (and far more relevant)

genomic question: Which of the thousands of long stretches of

repeated DNA in the human genome came first? And which are the

duplicates?

The answers, published online by Nature Genetics, provide the first

evolutionary history of the duplications in the human genome that

are partly responsible for both disease and recent genetic

innovations. This work marks a significant step toward a better

understanding of what genomic changes paved the way for modern

humans, when these duplications occurred and what the associated

costs are -- in terms of susceptibility to disease-causing genetic

mutations.

Genomes have a remarkable ability to copy a long stretch of DNA from

one chromosome and insert it into another region of the genome. The

resulting chunks of repeated DNA -- called " segmental duplications " -

- hold many evolutionary secrets and uncovering them is a difficult

biological and computational challenge with implications for both

medicine and our understanding of evolution.

The new evolutionary history, published in Nature Genetics, is from

an interdisciplinary team led by biologist Evan Eichler from the

University of Washington School of Medicine and computer scientists

Pavel Pevzner from University of California, San Diego.

In the past, the highly complex patterns of DNA duplication --

including duplications within duplications -- have prevented the

construction of an evolutionary history of these long DNA

duplications.

To crack the duplication code and determine which of the DNA

segments are originals (ancestral duplications) and which are copies

(derivative duplications), the researchers looked to both

algorithmic biology and comparative genomics.

" Identifying the original duplications is a prerequisite to

understanding what makes the human genome unstable, " said Pavel

Pevzner a UCSD computer science professor who modified an

algorithmic genome assembly technique in order to deconstruct the

mosaics of repeated stretches of DNA and identify the original

sequences. " Maybe there is something special about the originals,

some clue or insight into what causes this colonization of the human

genome, " said Pevzner.

" This is the first time that we have a global view of the

evolutionary origin of some of the most complicated regions of the

human genome, " said paper author Evan Eichler, a professor from the

University of Washington School of Medicine and the

Medical Institute.

The researchers tracked down the ancestral origin of more than two

thirds of these long DNA duplications. In the Nature Genetics paper

they highlight two big picture findings.

First, the researchers suggest that specific regions of the human

genome experienced elevated rates of duplication activity at

different times in our recent genomic history. This contrasts with

most models of genomic duplication which suggest a continuous model

for recent duplications.

Second, the researchers show that a large fraction of the recent

duplication architecture centers around a rather small subset

of " core duplicons " -- short segments of DNA that come together to

form segmental duplications. These cores are focal points of human

gene/transcript innovations.

" We found that not all of the duplications in the human genome are

created equal. Some of them -- the core duplicons -- appear to be

responsible for recent genetic innovations the in human genome, "

explained Pevzner, who is the director of the UCSD Center for

Algorithmic and Systems Biology, located at the UCSD division of

Calit2.

The authors uncovered 14 such core duplicons.

" We note that in 4 of the 14 cases, there is compelling evidence

that genes embedded within the cores are associated with novel human

gene innovations. In two cases the core duplicon has been part of

novel fusion genes whose functions appear to be radically different

from their antecedents, " the authors write in their Nature Genetics

paper.

" The results suggest that the high rate of disease caused by these

duplications in the normal population -- estimated at 1/500 and

1/1000 events per birth -- may be offset by the emergence of newly

minted human/great-ape specific genes embedded within the

duplications. The next challenge will be determining the function of

these novel genes, " said Eichler.

To reach these insights, the researchers worked to systematically

pinpoint the ancestral origin of each human segmental duplication

and organized duplication blocks based on their shared evolutionary

history.

Pevzner and his associate Haixu Tang (now professor at University of

Indiana) applied their expertise in assembling genomes from millions

of small fragments -- a problem that is not unlike the " mosaic

decomposition " problem in analyzing duplications that the team

faced.

Over the years, Pevzner has applied the 250-year old algorithmic

idea first proposed by 18th century mathematician Leonhard Euler (of

the fame of pi) to a variety of problems and demonstrated that it

works equally well for a set of seemingly unrelated biological

problems including DNA fragment assembly, reconstructing snake

venoms, and now dissecting the mosaic structure of segmental

duplications.

In the future, the researchers plan to continue their exploration of

evolution.

" We want to figure out how the human genome evolved. In the future,

we will combine what we know about the evolution within genomes with

comparative genomics in order to extend our view of evolution, " said

Pevzner.