COMPUTATIONAL GENOMICS

Challenges in human genetic diversity: demographic history and adaptation

Priyam Kumar(2011083)

Rachit Jain(2011084)

Rishabh Kwatra(2011087) .

Abstract
Genetic Diversity in Modern human is the result of
demographic history(study of human population in the
past) and selective effects that have acted to adapt dierent populations with respect to environment.Global Diversity can be explained on the basis of geographical location(geography),climate and many more factors.Global
Diversity Pattern is also based on out of africa model
of early human evolution.Natural Selection,climate,diet,
pathogens is responsible for population differences after
study is done on loci(specific location of a gene or DNA
sequence on a chromosome).

Introduction
Aim of human population genetics is to explain current
patterns of genetic diversity on the basis of population history and how humans adapted the enviroment or in other
words globe successfully.Goal is to study the effects/causes
of human genetic diversity. We will discuss developments
by studying human genetic diversity with the help of samples,computing FST on 2 population,SNP Plot and finally
dietary and climatic adaption by human population.

Figure 1: Human Karotype

netic differences have resulted in the striking variation seen

among individuals of ourspecies.

Human Genetic Diversity

Genetic Variation Factors

Genetic variation is the material basis of evolution, and

its origin and maintenance have long been the focus of population genetics and evolutionary biology. Charles Darwin
(1859) recognized the importance of variation in the origin
of species long before modern genetics began to emerge,
and numerous other early investigators noted that human
groups differ in skin color, hair form, body size, and other
physical characteristics.Humans are identical over most of
their genomes. Thus, only a relatively small number of ge-

Genetic variation describes naturally occurring genetic

differences among individuals of the same species. This
variation permits flexibility and survival of a population in
the face of changing environmental circumstances.

0.1 Mating
Mating can occur in two forms, with different consequences. One form of nonrandom mating isinbreeding,

which occurs when individuals with similar genotypes are

more likely to mate with each other rather than with individuals with different genotypes.
The second form of nonrandom mating is calledoutbreeding, wherein there is an increased probability that individuals with a particular genotype will mate with individuals of another particular genotype. Whereas inbreeding can lead to a reduction in genetic variation, outbreeding
can lead to an increase.

0.2 Genetic Drift

Genetic drift basically refers to the random fluctuations
in allele frequency over generations due to random sampling. It allows allele frequency to change over time due to
chance. It can also cause harmful alleles to become fixed
(by chance) Once genetic drift begins in a population, it
eventually leads to a decrease in genetic diversity. Genetic
drift can also result in the loss of rare alleles, which get
lost due to population bottleneck, a scenario when an entire
population (or a huge part of it) gets wiped out due to environmental factors. This can decrease the size of the gene
pool. The Founder effect is another type of Genetic Drift.
Here, a few individuals become isolated from a larger population and the smaller group may establish a new population whose gene pool differs from the source population.

0.3 Distribution
A species with a broad distribution rarely has the same
genetic makeup over its entire range. For example, individuals in a population living at one end of the range may
live at a higher altitude and encounter different climatic
conditions than others living at the opposite end at a lower
altitude. What effect does this have? At this more extreme
boundary, the relative allele frequency may differ dramatically from those at the opposite boundary. Distribution is
one way that genetic variation can be preserved in large
populations over wide physical ranges, as different forces
will shift relative allele frequencies in different ways at either end.
If the individuals at either end of the range reconnect
and continue mating, the resulting genetic intermixing can
contribute to more genetic variation overall. However, if
the range becomes wide enough that interbreeding between
opposite ends becomes less and less likely, and the different forces acting at either end become more and more pronounced, and the individuals at each end of the population
range may eventually become genetically distinct from one
another.

0.4 Migration
Migration basically is the transfer of alleles from gene
pool of one population to the other. Allele frequency will
change if migration occurs into or away from the population. It is more possible in animals than plants as they are
mobile and hence more capable of meeting genetically distinct species. Gene flow or migration leads to combining
of two gene pools, and even though this reduces variation,
it helps maintain genetic diversity. After mating is established between the migrating and destination individuals,
the migrating individuals will contribute gametes carrying
alleles that can alter the existing proportion of alleles in the
destination population.

Locus and Allele

0.1 Locus
Locus (loci) is the specific location of a gene or DNA
sequence on a chromosome. Also, Gene Mapping is used
to determine locus for a particular biological trait.

0.2 Allele
One of a number of alternative forms of the same gene
or same genetic locus (generally a group of genes). different alleles can result in different observable phenotypic
traits, such as different pigmentation. However, many variations at the genetic level result in little or no observable
variation.

Fixation Index
The fixation index is the average coefficient of inbreeding in a population. In case of random mating, the probability that an offspring would have exactly the same two
ancestral alleles at a locus is (1/2)N, where N is the number of diploid individuals in the population. The probability of having two different alleles at the same locus is
1 (1/2)N. The coefficient of inbreeding of the first generation of this population is also (1/2)N by definition of
inbreeding. In each succeeding generation, the non-inbred
part of the population will have a chance to produce offspring with an allele pair identical by descent. Therefore,
the coefficient of inbreeding in the next generations will be
(1/2)N + [(1 (1/2)N] x F, where F is the inbreeding coefficient of the preceding generation. After the gth generation
the coefficient of inbreeding of this population will be: Fg
= (1/2)N + [1 (1/2)N]Fg1 and this is called the index of
fixation.

Figure 3: Fst for two population

Figure 2:

Figure 2
The values of Fst for pairwise population comparisons
of 34 genes among the three most commonly defined human continental population groups (African, Asians, and
Europeans) are shown in Figure 2.If the value fell within
the 95(Cavalli-Sforza et al. 1994) value, then the degree of
genetic diversity for this gene between these two populations was considered to be not significantly different from
that expected from the reference value (indicated as R in
the table). Values greater than the upper confidence limit
could reflect the effects of positive or diversifying natural selection leading to increased diversity between populations. Values of Fst below the 95on the other hand, might
result from balancing selection (especially for alleles at or
near fixation), or could be due to chance.

Using FST on two population

Here we are comparing the allele frequencies of two
populations and the data used in this is the fasta sequence
of of chromosome 2R of D.melanogaster.Around 10,000
SNPs have been located.Simulation of different allele frequencies for these SNPs is done in 2 population with difference in the range of 0.1 to 0.9.For simulation, software
used are as follow - Perl,bwa,samtools,IGV(for plot) and
popoolation for sample. First step is to prepare the genome
and then map to the reference genome.After mapping has
been done, remove ambious mapped reads and then creating a synchronized file(which took around 45 mins to
done). When synchronized file has been created,then we
have calculated the allele frequency differences which in
thus created two output files with one file (rc file) consisting of major and minor alleles for every SNP and other

file(pwc file) contains the differences in allele frequencies

for every pairwise comparison of the populations present
in the synchronized file.Now comes the main part, Fst has
been calculated for every SNP of pool size 500.Now Fst file
is converted into IGV format.After computing and conversion, file is loaded into IGV and loaded files in IGV are 2R.fasta,two .bam files and finally .igv file(fst values).

Figure 4: Fst with file of windows size500

Calculating FST for genes

For computing FST for genes,we use chromosome 2R
again and convert this file into gene based file.After converting into gene based file,we compute Fst for every
gene.Following figure5 shows output for genes.For example in figure5 gene CG17683-RA 500000 has computed
FST = 0.01359409 and for gene CG17683-RE 500000 has
computed FST = 0.01359409.

SNP
We took samples from 1000genome project with following constraints Linkage Disequilibrium Data Focus:
Variant rs311685 (dbSNP 137)

Figure 5: Computed FST for genes

Figure 7:

Figure 6:

Figure 8:

Figure 9:

Prediction method: LD values were calculated by

a pairwise estimation between SNPs genotyped in the
same individuals and within a 100kb window. An established method was used to estimate the maximum
likelihood of the proportion that each possible haplotype contributed to the double heterozygote. Location :
6:74115888-74135887 Populations: Population: CSHLHAPMAP:HapMap-CEU Description: Utah residents with
Northern and Western European ancestry from the CEPH
collection. then we computed circular genome data ,
plot of the -log10 P values by chromosome of the data
via GWASrap. then graph of SNp (LD Map Type: rsquare,D)is plotted with the help of the given samples

Figure 10:
Figure 12: rs12213727

Figure 13: rs12209309

Figure 11: rs6928023

Adaption to Environment
0.1 Climate
They refer to adaptations in a living organism in response to change in climate, habitat and surroundings.
This includes physical changes like the change in skin/fur
color; or behavioral changes like hibernating during winters. Africans, living in the tropics were exposed to direct sunlight, which meant a darker skinned population.
On the other hand, the migrants settled in colder environments, with lesser sunlight, resulting in a lighter skin tone.
Bergmanns Rule
It states that populations having less massive individuals
are more often found in warm climates near the equator,
while those with greater mass, are found further from the
equator in colder regions. This is due to the fact that big
animals generally have larger body masses which result in
more heat being produced. The greater amount of heat results from there being more cells. A normal byproduct of
metabolism in cells is heat production. Subsequently, the
more cells an animal has, the more internal heat it will produce. Also, larger animals usually have a smaller surface
area relative to their body mass and, therefore, are comparatively inefficient at radiating their body heat off into the
surrounding environment.
Allens Rule
He noted that among warm-blooded animals, individuals
in populations of the same species living in warm climates
near the equator tend to have longer limbs than populations living further away from the equator in colder environments. This is due to the fact that a body with relatively long appendages is less compact and subsequently
has more surface area. Greater the surface area, the faster
body heat will be lost to the environment.

0.2 Diet
A dietary adaptation is a morphological trait of a species
which relates to the diet of the species.
For example, the shape of primate molars and premolars are adapted to the diet of the species, Insectivores
have pointed teeth for piercing insect exoskeletons Herbivores have ridged teeth which cut teeth in a scissor-like
fashion Dietary adaptations arent just limited to the teeth.
Cows have evolved a stomach which has 4 compartments;
the rumen, the reticulum, the omasum and the abomasum,
which allows for increased efficiency of plant matter digestion compared to a simple stomach. There are many
differences in how effectively our bodies process particular
foods. Some people live a healthy life on diets that would
be at a starvation level for others. Also people eat different
food to suit the surroundings. For example, people living

at colder regions eat more fat than other populations can

digest, just to maintain their body temperature. A major
dietary adaptation is related to lactase. Most people from
Africa, East Asia, and among Native Americans have lactose intolerance, which results in them not being able to
digest dairy products, due to lactase deficiency. Northern
Europeans generally have the lowest frequency of this dietary problem.

Contribution
Rachit conceived the idea and organized it , and surfed
the net for data of SNP and Fst, downloaded the data and
found out softwares to compute the data and generated
the result of Snp. Priyam performed the analysis of fst
and generated the results of FST using perl and surfed the
net for Human genetic factors. Rishabh has done work
on adaptation and genetic factors(only theory). All three
wrote paper on basis of work done by each. Priyam converted the proposal and report in IEEE format.

References
[1] Jobling M.A., Hurles M.E., Tyler-Smith C. Human
Evolutionary Genetics: Origins, Peoples and Disease.
New York, Abingdon: Garland Science; 2004.
[2] Rosenberg N.A. Standardized subsets of the HGDPCEPH Human Genome Diversity Cell Line Panel, accounting for atypical and duplicated samples and pairs
of close relatives. Ann. Hum. Genet. 2006;70:841-847.
[3] bio-bwa.sourceforge.net/
[4] samtools.sourceforge.net/
[5] www.broadinstitute.org/igv/
[6] 1000genomes.org