written by NIKKI BREAUX
Ancestral Origins
New Software Looks Even Further Into the Past
Many preconceptions about
individuals start with the assumption that a
person’s ethnicity can be judged by simply
looking at his or her physical traits. Eyes,
skin, even hair all yield clues about the
origin of a person’s family. But in the lab of
Dr. Serafim Batzoglou, assistant professor
in the Department of Computer Science,
ancestral analysis goes much deeper. Dr.
Batzoglou and graduate students Eugene
Fratkin, Andreas Sundquist and Chuong Do
have developed software that can pinpoint
the ethnicity of ancestors from ten or even
twenty generations ago by looking at
the historical information buried in their
descendant’s DNA. How was this level of
precision achieved, and what can it tell us
about our ancestry?
Clues Hidden In the
DNA
The idea of developing software capable
of identifying the contribution of different
A map of human migrations based
on mitochondrial DNA, with dates
denoting time before present.
Populations are described by mtDNA
haplogroups: African: L, L1, L2, L3,
Near Eastern: J, N, Southern European:
J, K, General European: H, V, Northern
European: T, U, X, Asian: A, B, C, D, E,
F, G (note: M is composed of C, D, E,
and G) Native American: A, B, C, D, and
sometimes X
ethnicities in a multi-ethnic, or “admixed”
individual was conceived as part of
Dr. Batzoglou’s consulting work with
23andme, a Bay Area genetic analysis
company. Dr Batzaglou explains: “The
problem of determining the ancestral
population for each location of an
individual’s chromosomes appealed to
us as scientifically interesting, and one in
which we could contribute computational
methods that are substantial improvements
over the state of the art.”
The new software was named “HAPAA,”
a play on the term “Hapa” used in Hawaii
to describe a person of mixed ethnic
origin. Race and ethnicity have been used
throughout history as defining, if not
divisive, characteristics; conflicts between
ethnic groups have triggered many of the
worst battles in human history. But the
concept of racial identity is far from simple.
One of the most visible clues to racial
identity, skin color, is more closely related
to geographic distance from the equator
than shared ancestry. Racial groups are, in
truth, extremely similar at the genetic level.
Research has shown that, on average, only
0.1% of DNA will differ between any two
individuals. Of this 0.1%, only 10-15% varies
between groups of different ethnic origin;
most of the remaining genetic diversity
contributes to variety within a population
of shared ethnic origin. Included in that 10%
are genes containing small mutations that
accumulate over generations.
A Haploblock Mosaic
HAPAA was designed to analyze patterns
of change in sequences of DNA from
different populations over long periods of
time. Random single nucleotide mutations,
called “SNPs,” appear frequently, scattered
throughout human chromosomes. If the
mutations are not harmful, they may escape
the ravages of natural selection and be
Mitomap.org
volume VII 39
 ENG + TECH written by NIKKI
RORY BREAUX
SAYRES

How closely does the American

population resemble these ancestral
populations?
This question has been posed and answered through several lines
of research. In one study led by Dr. Shriver, Associate Professor
of Anthropology and Genetics at Pennsylvania State University
research, a sample population in Chicago was analyzed using an
older genetic analysis method. Dr. Shriver’s results determined
that admixture was very common, especially among the African-
American and Hispanic populations. Among the average subject
who self-described as “white,” there was a 0.7% African Ancestry,
while the average African American had 15-18% European genetic
ancestry. A different team of scientists, led by Cerda-Flores of the
National Autonomous University of Mexico, found that the average
Hispanic American had 3-8% African ancestry. These estimates,
however, were only able to detect the ethnicity of the previous 7
generations, which strongly reflected the forced migrations of slave
populations to the Americas. HAPAA has the power to look at trace
ancestral history over 20 generations, before America was colonized
by Europeans.

inherited by successive generations. Because positions in a genotype; our method can

they differ between many individuals, SNPs
function as “markers” for different ancestral
histories.
The HAPAA program identifies groups of
SNPs found in unique regions of the DNA
that are usually inherited together over
multiple generations. These collections of
multiple SNP markers, called “haploblocks,”
are eroded over generational time by
mutations and recombination. The
haploblocks of a child born in 2000 will look
like a genetic mosaic, a fragmented version
of the haploblocks of his 20th generation
ancestors.
The predictive power of HAPAA relies on
Adapted from Parra EJ, et al. Nature Genetics 36, S54 - S60 (2004)
utilize LD patterns of arbitrary genomic
distances.” This difference expanded the
predictive power of the model, allowing
HAPAA to look ten generations into the past,
while maintaining a low error rate.
Taking Apart the Mosiac
Identifying a haploblock in an individual
is the first step in inferring ancestry. This
haploblock would most likely be found
interspersed with bits of other haploblocks
due to various recombination events. Those
small fragments of the original haploblock,
however, are enough to backtrack to the
ancestral DNA sequence. Before taking
on the challenge of looking at current
populations, however, Dr Batzoglou and

Triangular representation of the
average West African, European and
Indigenous American admixture pro-
portions of different populations.
“linkage disequilibrium” between the SNPs
in each haploblock. Linkage disequilibrium
(LD) refers to the likelihood of certain
genetic combination being found in the
same individual. For example, consider two
genes A and B, which exist as versions A
and A’, as well as B and B’. If the two genes
sorted independently during mating, then
an individual with A or A’ will have the
same probability of having B or B’; genes
A and B would therefore be considered to
be in “linkage equilibrium.” However, genes
often sort in linkage disequilibrium, with
a disproportionate number of individuals
inheriting a specific combination, for
example A with B, or A’ with B’.
Other genome software take advantage of
linkage disequilibrium, but HAPAA takes the
analysis several steps further. According to
Dr. Batzaglou, “previous methods could only
take into account LD between neighboring
his lab had to train HAPAA to identify the
fragments of the ancestral haploblock
and retrace the lineage that produced the
current admixture.
As a starting point for the development of
the HAPAA program, Dr Batzoglou drew
upon the DNA sequences found in HapMap,
a database of genetic variants found in
different individuals. 210 DNA sequences,
representing nearly unrelated individuals of
North Western European, West African and
East Asian ancestry, were drawn from this
database and used as the “training set” for
HAPAA. A smaller group of these individuals
was withheld for testing of the finalized
program.
In order to build greater predictive power
into HAPAA, graduate students simulated
successive mating over 20 generations
of individuals drawn at random from the

40 stanford scientific

Other genome software
take advantage of linkage
disequilibrium, but HAPAA takes
the analysis several steps further.
training set. The model assumed that, as
in real life, there was a small degree of
recombination and genetic drift (a random
skew in gene frequencies that happens
over time). By knowing the ancestries of
every fragment in the mosaic pattern of the
resultant haploblocks in each generation,
HAPAA could be trained to infer the patterns
of inheritance across multiple generations.
After many rounds of training, HAPAA was
ready for its final testing. Dr Batzoglou and
his students created simulated individuals
from the test set withheld from training.
These individuals were the result of multiple
rounds of simulated mating and each had
only a single ancestor from one ethnic
group, while all other ancestors were
drawn from a different ethnic group. The
challenge was for HAPAA to identify the
location of the contributions of the two
different ethnicities. The results of these
tests indicated that HAPAA could determine
with high accuracy the contribution of a
single ancestor within the previous ten
generations. The prediction was more
accurate when the two populations sampled
were assumed to be highly divergent. The
more genetically similar the two populations
were, the more difficult it became to detect
the contribution of the single ancestor.
However, in populations separated by a
large amount of time, the contribution of a
20th generation ancestor could be detected.
Mapping Human
Migrations
The Batzaglou lab is currently working
to make HAPAA available to the general
public. Although HAPAA can currently
layout by RORY SAYRES
Credit: sxc.com
distinguish contributions from an was
ancestor 20 generations prior to his or her very
descendant, its predictive power is limited common,
to the ethnic groups used in the training especially
set. Dr. Batzaglou would like to see further among the
improvements, “making it more effective on African-American and
fine-grained distinctions between highly Hispanic populations. Among
similar populations” such that the program the average subject who was
could distinguish between as many as the self-described as “white,” there was a 0.7%
50 different populations on Earth. He can African Ancestry, while the average African
also foresee wide-reaching applications American had 15-18% European genetic
of the software. As he explains, “imagine ancestry. A different team of scientists,
several thousand individuals from different led by Cerda- Flores of the Universidad
neighboring populations having their Nacional Autónoma de México, found that
ancestry painted in their chromosomes the average Hispanic American had 3-8%
using HAPAA. The statistics of the ancestral African ancestry. These estimates, however,
blocks could tell us about the history, were only able to detect the ethnicity of
migration and admixture patterns of the the previous seven generations, which
nearby populations in the past several strongly reflected the forced migrations of
hundred years.” slave populations to the Americas. HAPAA
has the power to look at trace ancestral
Admixed America history over 20 generations, before America
How closely does the American population was colonized by Europeans.
resemble these ancestral populations? This
question has been posed and answered
through several lines of research. In
one study led by Dr. Shriver, Associate
Professor of Anthropology and Genetics
at Pennsylvania State University, a sample
population in Chicago was analyzed using
an older genetic analysis method. Dr.
Shriver’s results determined that admixture
Nikki Breaux is a PhD student researching cancer biology. In her free time, she enjoys
reading, cycling and enjoying Califonia’s weather.
To Learn More
For more information, visit Dr. Batzaglou’s departmental website at http://ai.stanford.
edu/~serafim/. Additional literature and discussion about race and genetics can be
found at http://raceandgenomics.ssrc.org/.
volume VII 41