Human Genetic Variation Seile Yohannes, H3ABioNet/H3Africa College of Natural & Computational Science, Jigjiga University, Ethiopia

Jigjiga University

Learning Objectives Define Human Genetic Variation Understand the basis of Human Genetic Variation- DNA Sequence Variation Origins of DNA Sequence Variation Mutation- the ultimate source of variation Others- Recombination, Gene flow, Genetic Drift Types of DNA Sequence Variation Single Nucleotide Variations (SNVs) Copy Number Variations (CNVs) Structural Variations

Introductory Points Chromosomes Historical Aspects Structural & functional aspects

What are Chromosomes? Chromosomes: Historical Aspects “The blueprint” of life- house the genetic material (DNA) Their discovery and functional exploration coincides with the era of “modern history of genetics”- 1842-1900

Chromosomes… First noticed by C. von Nägeli in 1842 Pollen cell experiments Importance of the nucleus

Chromosomes… Mendel’s experiment (1858-1866)- his “traits” indicated that inheritance is linked to transmission of “alleles”- implying involvement of cellular components

Chromosomes… Walther Flemming’s experiments (1879-1885)- with the aid of new staining techniques, described the chromosomes Way they moved during division (mitosis) Separation & movement of sister chromatids to opposite poles Defined the processes of “Mitosis” and “Meiosis”

Chromosomes… W. Waldeyer (1888) Coined the term “chromosomes” to describe the structures studied by Flemming Greek word- “Chroma”- colored; “Soma”- body = “Colored body”- to describe the deeply staining properties of these structures during cytological analysis

Chromosomes… In 1903-1911, Walter Sutton & Theodore Boveri Studied meiosis (gamete formation) Hypothesized that the behavior of chromosomes during meiosis explained Mendel’s rules of inheritance Discovery that genes are located on chromosomes- “chromosomal theory of inheritance”…………

Chromosomes: from gamete formation to fertilization

Gamete formation- Meiosis Reductional division- reduces the number of chromosomes by half- from diploid (2n) to haploid (n)

Restoration of diploid state- Fertilization

Genetic Diversity & Human Genetic Variation Heritable variations both within and between populations Imply that there are genetic polymorphisms- Multiple variants of any given gene in the human population Manifested as polymorphisms of sequences of the 4 different bases that make up the gene Vis-à-vis the DNA Nucleotide

Genetic Variation Describes differences between DNA sequences of individual genomes. As each individual has two nuclear genomes (a paternal genome and a maternal genome), genetic variation occurs within as well as between individuals.

Genetic Variation Broadly categorized into 2 classes based on time of origin of the variation: Constitutional Genetic Variation:- caused by changes occurring in parental genomes and/or during formation of offspring and thus inherited and present within the genome of the organism during birth Post-Zygotic or Somatic Genetic Variation- caused by changes occurring after birth throughout the life of he individual, and causing minor polymorphisms among the different cells of the same individual.

Genetic Variation: Cause The ultimate cause of genetic variation is DNA sequence change DNA sequence variation is caused by: Mutation Others- Recombination, Gene Flow, Genetic drift We will only highlight on the “other” causes briefly

Mutation Structural change of a gene that leads to a variant form caused by the alteration of single base units in DNA, or the deletion, insertion, or rearrangement of larger sections of genes or chromosomes Occur spontaneously as a result of errors in DNA replication or induced by exposure to radiation or chemicals (Mutagens)

Mutations- classification 2 broad classes based on pattern of occurrence in the genome Gene Mutations Chromosomal Mutations 2 distinctions based on the type of cell they occur Somatic Mutations Germ-line Mutations

Gene Mutations Mutations that only affect a single gene 3 types: Insertion –one or more nucleotides are added within a DNA sequence for a gene Deletion –one or more nucleotides are removed from a DNA sequence for a gene Substitution (point mutation) –a nucleotide is replaced with a different nucleotide

Type Definition Example Insertion A new nucleotide is added …TAGCCAGATA… …TAGCGCAGATA… Deletion A nucleotide is removed …TAGCAGATA… Substitution (point mutation) A nucleotide is replaced with a different nucleotide …TAGCCAGTTA…

Chromosomal Mutations Mutations that affect multiple genes Structural mutations/abnormaities Chromosomal Mutations Deletions Translocations Inversions Duplications

Small or large & in one or more genes Deletions Loss of chromosomal material Small or large & in one or more genes Example: Cri du chat syndrome Deletion of short arm of chromosome 5 Affects motor and mental function Specific chromosomal break points are associated with specific phenotypic changes

Translocations Exchange of chromosomal segments between nonhomologous chromosomes Two major types Reciprocal translocation Non-reciprocal translocation

Types of Translocations

Types of Translocations Robertsonian Translocation Special form of reciprocal translocation Centromeres from two non-homologous chromosomes fuse and chromosomal material from the short arms is lost 5% of Down syndrome cases involve a Robertsonian translocation between chromosomes 21 and 14

Robertsonian Translocation A translocation between chromosome 14 and 21 may produce: Translocation carrier Normal phenotype Translocation Down syndrome Lethal monosomy 21 Lethal trisomy 14 Lethal monosomy 14 Fig. 6.27 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning

Inversions Inversion of chromosomal segment 2 types:

Chapter 6 Human Heredity by Michael Cummings ©2006 Brooks/Cole-Thomson Learning

Duplication Duplication /multi-copy formation/ of chromosomal segment 3 forms: Tandem Reverse Tandem Terminal Tandem

Somatic Mutations Occur in cells of the body that do not form gametes Occur during mitosis Are not transmitted to future generations

Germ-line Mutations Occur in cells of the body Producing gametes Occurs during meiosis Are heritable changes that are transmitted to future generations

Types of DNA Sequence Variation Single Nucleotide Variations (SNVs) Variations occurring at a single nucleotide in somatic cells When their frequency in a population is delineated, then SNVs are referred to as single nucleotide polymorphisms (SNPs) SNPs- Most common type of sequence variation (account for 90% of all sequence variation) Other sequence variations are single base exchanges, deletions and insertions (discussed in previous sections)

Other Sources of Genetic Variation

Recombination (Crossing-over) during gamete formation A process that occurs when two homologous chromosomes align during meiosis and exchange a segment of genetic material. A natural process by which diversity is increased via gametic variation

Here, the alleles for gene C were exchanged Here, the alleles for gene C were exchanged. The result is two recombinant and two non-recombinant chromosomes. https://www.boundless.com/

Other population dynamics factors contributing to variation… Gene Flow… Genetic Drift…

Thank You…