Human genetic diversity is largely due to minor variations in DNA, with only about 0.5% of the sequence differing between unrelated individuals. These genetic differences can influence various traits, predispositions to diseases, and responses to medications, while mutations and polymorphisms play key roles in genetic variation. The document discusses types of mutations, their origins, and implications for personalized medicine and genetic research.

1. GENETICS
Human Genetic Diversity: Mutation and Polymorphism

2. GENETIC DIVERSITY
The sequence of nuclear DNA is approximately 99.5% identical between any two
unrelated humans. Yet it is precisely the small fraction of DNA sequence difference
among individuals that is responsible for the genetically determined variability that is
evident both in one’s daily existence and in clinical medicine.
Many DNA sequence differences have little or no effect on outward appearance, whereas
other differences are directly responsible for causing disease.
Between these two extremes is the variation responsible for genetically determined
variability in anatomy, physiology, dietary intolerances, susceptibility to infection,
predisposition to cancer, therapeutic responses or adverse reactions to medications, and
perhaps even variability in various personality traits, athletic aptitude, and artistic talent.

3. THE NATURE OF GENETIC VARIATION
Segment of DNA occupying a particular position or location on a chromosome is a
locus (plural loci).
A locus may be large, such as a segment of DNA that contains many genes, such
as the major histocompatibility complex locus involved in the response of the
immune system to foreign substances; it may be a single gene, such as the or it
may even be just a single base in the genome, as in the case of a single nucleotide
variant.
Alternative versions of the DNA sequence at a locus are called alleles. For many
genes, there is a single prevailing allele, usually present in more than half of the
individuals in a population, that geneticists call the wild-type or common allele.

4. THE NATURE OF GENETIC VARIATION
The other versions of the gene are variant (or mutant) alleles that differ from the
wild-type allele because of the presence of a mutation, a permanent change in the
nucleotide sequence or arrangement of DNA.
If there are two or more relatively common alleles (defined by convention as
having an allele frequency > 1%) at a locus in a population, that locus is said to
exhibit polymorphism (literally “many forms”) in that population.
Most variant alleles, however, are not frequent enough in a population to be
considered polymorphisms; some are so rare as to be found in only a single family
and are known as “private” alleles.

5. THE NATURE OF GENETIC VARIATION
"Allele" is the word that we use to describe the alternative form or versions of a
gene. People inherit one allele for each autosomal gene from each parent, and we
tend to lump the alleles into categories.
Typically, we call them either normal or wild-type alleles, or abnormal, or mutant
alleles.
If you have two blue eye alleles, your eyes will be blue. But if you have one allele
for blue eyes and another for brown eyes, your eye color will be dictated by
whichever allele is dominant. A dominant allele is one that always determines the
phenotype when present.

6. MUTATIONS
Mutations are sometimes classified by the size of the altered DNA sequence and, at
other times, by the functional effect of the mutation on gene expression. Although
classification by size is somewhat arbitrary, it can be helpful conceptually to distinguish
among mutations at three different levels:
• Mutations that leave chromosomes intact but change the number of chromosomes in a
cell (chromosome mutations)
• Mutations that change only a portion of a chromosome and might involve a change in
the copy number of a subchromosomal segment or a structural rearrangement involving
parts of one or more chromosomes (regional or sub chromosomal mutations)
Alterations of the sequence of DNA, involving the substitution, deletion, or insertion of
DNA, ranging from a single nucleotide up to an arbitrarily set limit of approximately 100
kb (gene or DNA mutations)

7. POLYMORPHISM
Allelic variants can be used as “markers” for tracking the inheritance of the corresponding
segment of the genome in families and in populations. Such variants can be used as follows:
• As powerful research tools for mapping a gene to a particular region of a chromosome by
linkage analysis or by allelic association
• For prenatal diagnosis of genetic disease and for detection of carriers of deleterious alleles , as
well as in blood banking and tissue typing for transfusions and organ transplantation
• In forensic applications such as identity testing for determining paternity, identifying remains of
crime victims, or matching a suspect’s DNA to that of the perpetrator (this chapter)
• In the ongoing efforts to provide genomic-based personalized medicine in which one tailors an
individual’s medical care to whether or not he or she carries variants that increase or decrease
the risk for common adult disorders (such as coronary heart disease, cancer, and diabetes; or
that influence the efficacy or safety of particular medications

8. Single Nucleotide Polymorphisms
The simplest and most common of all polymorphisms are single nucleotide
polymorphisms (SNPs). A locus characterized by a SNP usually has only two
alleles, corresponding to the two different bases occupying that particular location
in the genome .
As mentioned previously, SNPs are common and are observed on average once
every 1000 bp in the genome. However, the distribution of SNPs is uneven around
the genome; many more SNPs are found in non coding parts of the genome, in
introns and in sequences that are some distance from known genes.
Nonetheless, there is still a significant number of SNPs that do occur in genes and
other known functional elements in the genome.

9. Insertion-Deletion Polymorphisms
A second class of polymorphism is the result of variations caused by insertion or
deletion (in/dels or simply indels) of anywhere from a single base pair up to
approximately 1000 bp, although larger indels have been documented as well.
Over a million indels have been described, numbering in the hundreds of
thousands in any one individual’s genome.
Approximately half of all indels are referred to as “simple” because they have only
two alleles—that is, the presence or absence of the inserted or deleted segment

10. Mobile Element Insertion Polymorphisms
Nearly half of the human genome consists of families of repetitive elements that are dispersed around the
genome.
Although most of the copies of these repeats are stationary, some of them are mobile and contribute to
human genetic diversity through the process of retrotransposition, a process that involves transcription
into an RNA, reverse transcription into a DNA sequence, and insertion ( transposition) into another site in
the genome, as we introduced in Chapter 3 in the context of processed pseudogenes.
The two most common mobile element families are the Alu and LINE families of repeats, and nearly
10,000 mobile element insertion polymorphisms have been described in different populations. Each
polymorphic locus consists of two alleles, one with and one without the inserted mobile element .
Mobile element polymorphisms are found on all human chromosomes; although most are found in non
genic regions of the genome, a small proportion of them are found within genes.

11. THE ORIGIN AND FREQUENCY OF DIFFERENT TYPES
OF MUTATIONS
Along the spectrum of diversity from rare variants to more common
polymorphisms, the different kinds of mutations arise in the context of such
fundamental processes of cell division as DNA replication, DNA repair, DNA
recombination, and chromosome segregation in mitosis or meiosis.
The frequency of mutations per locus per cell division is a basic measure of how
error prone these processes are, which is of fundamental importance for genome
biology and evolution.
people with a disease-causing mutation may manifest the condition only late in
life or may never show signs of the disease.

12. DE NOVO MUTATIONS
The major types of mutation briefly introduced earlier occur at appreciable
frequencies in many differ¬ ent cells in the body. In the practice of genetics, we are
principally concerned with inherited genome variation; however, all such variation
had to originate as a new (de novo) change occurring in germ cells.
Although the original mutation would have occurred only in the DNA of cells in the
germline, anyone who inherits that mutation would then carry it as a constitutional
mutation in all the cells of the body.

13. SOMATIC MUTATIONS
In contrast, somatic mutations occur throughout the body but cannot be
transmitted to the next generation.
Given the rate of mutation (see later in this section), one would predict that, in fact,
every cell in an individual has a slightly different version of his or her genome,
depending on the number of cell divisions that have occurred since conception to
the time of sample acquisition.
In highly proliferative tissues, such as intestinal epithelial cells or hematopoietic
cells, such genomic heterogeneity is particularly likely to be apparent.
However, most such mutations are not typically detected, because, in clinical
testing, one usually sequences DNA from collections of many millions of cells;

14. CHROMOSOME MUTATIONS
Mutations that produce a change in chromosome number because of chromosome
missegregation are among the most common mutations seen in humans, with a rate of
one mutation per 25 to 50 meiotic cell divisions.
This estimate is clearly a minimal one because the developmental consequences of
many such events are likely so severe that the resulting fetuses are aborted
spontaneously shortly after conception without being detected.
Mutations affecting the structure or regional organization of chromosomes can arise in a
number of different ways. Duplications, deletions, and inversions of a segment of a single
chromosome are predominantly the result of homologous recombination between DNA
segments with high sequence homology located at more than one site in a region of a
chromosome.

15. DNA REPLICATION ERRORS
The process of DNA replication is typically highly accurate; the majority of replication
errors (inserting a base other than the complementary base that would restore the base
pair at that position in the double helix) are rapidly removed from the DNA and corrected
by a series of DNA repair enzymes that first recognize which strand in the newly
synthesized double helix contains the incorrect base and then replace it with the proper
complementary base, a process termed DNA proofreading.
DNA replication needs to be a remarkably accurate process; otherwise, the burden of
mutation on the organism and the species would be intolerable.
The enzyme DNA polymerase faithfully duplicates the two strands of the double helix
based on strict base-pairing rules (A pairs with T, C with G) but introduces one error every
10 million bp.

16. TYPES OF MUTATIONS AND THEIR CONSEQUENCES
Missense Mutations
A single nucleotide substitution (or point mutation) in a gene sequence, such as
that observed in the example of achondroplasia, can alter the code in a triplet of
bases and cause the nonsynonymous replacement of one amino acid by another
in the gene product.
Achondroplasia is a bone growth disorder that results in dwarfism due to a genetic
mutation in the arms and legs. Achondroplasia is the most common form of short
stature
Such mutations are called missense mutations because they alter the coding (or
“sense”) strand of the gene to specify a different amino acid.

17. NONSENSE MUTATIONS
Point mutations in a DNA sequence that cause the replacement of the normal codon for
an amino acid by one of the three termination (or “stop”) codons are called nonsense
mutations.
Because translation of messenger RNA (mRNA) ceases when a termination codon is
reached , a mutation that converts a coding exon into a termination codon causes
translation to stop partway through the coding sequence of the mRNA. The
consequences of premature termination mutations are twofold.
First, the mRNA carrying a premature mutation is often targeted for rapid degradation
(through a cellular process known as nonsense-mediated mRNA decay), and no
translation is possible.
And second, even if the mRNA is stable enough to be translated, the truncated protein is
usually so unstable that it is rapidly degraded within the cell

18. Deletions, Insertions, and Rearrangements
Mutations can also be caused by the insertion, deletion, or rearrangement of DNA
sequences. Some deletions and insertions involve only a few nucleotides and are
generally most easily detected by direct sequencing of that part of the genome.
In other cases, a substantial segment of a gene or an entire gene is deleted, duplicated,
inverted, or translocated to create a novel arrangement of gene sequences. Depending
on the exact nature of the deletion, insertion, or rearrangement, a variety of different
laboratory approaches can be used to detect the genomic alteration.
Some deletions and insertions affect only a small number of base pairs. When such a
mutation occurs in a coding sequence and the number of bases involved is not a multiple
of three

19. Deletions, Insertions, and Rearrangements
Alternatively, such mutations can lead to a change in the nature of the encoded
protein itself when recombination occurs between different genes within a gene
family ( or between genes on different chromosomes.
Abnormal pairing and recombination between two similar sequences in opposite
orientation on a single strand of DNA leads to inversion.
For example, nearly half of all cases of hemophilia A are due to recombination that
inverts a number of exons, thereby disrupting gene structure and rendering the
gene incapable of encoding a normal gene product