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

2. Jigjiga University

3. 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

4. Introductory Points Chromosomes Historical Aspects
Structural & functional aspects

5. 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”

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

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

8. 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”

9. 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

10. 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”…………

11. Chromosomes: from gamete formation to fertilization

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

14. Restoration of diploid state- Fertilization

15. 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

16. 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.

17. 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.

18. 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

19. 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)

20. 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

21. 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

22. 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…

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

24. 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

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

26. Types of Translocations

27. 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

28. 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

29. Inversions
Inversion of chromosomal segment
2 types:

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

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

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

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

36. 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)

37. Other Sources of Genetic Variation

38. 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

39. 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.

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

41. Thank You…