Lecture 1 Recombination_ Homologous Recombination (Final).pptx

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1. Recombination: Homologous Recombination

2. Contents Recombination Definition Types Crossing Over Homologous Chromosomes Homologous Recombination History and Discovery Significance in Eukaryotes, Bacteria and Viruses Dysfunction in Homologous Recombination Summary References

3. Recombination Recombination is a process by which pieces of DNA are broken and recombined to produce new combinations of alleles. It creates genetic diversity at the level of genes that reflects differences in the DNA sequences of different organisms. During meiosis in eukaryotes, genetic recombination involves the pairing of homologous chromosomes .

4. Recombination occurs randomly in nature as a normal event of meiosis. It is enhanced by the phenomenon of crossing over, in which gene sequences called linkage groups are disrupted. This disruption results in an exchange of segments between paired chromosomes that are undergoing separation. This justifies that meiosis results in daughter cells which are not alike despite having half of the genetic material from the parent.

5. Types Homologous recombination Non homologous recombination Site specific recombination Replicative recombination

6. Homologous Recombination

7. Homologous Chromosomes Each diploid cell contains two copies of every chromosome, one derived from the maternal gamete and the other from the paternal gamete. These pairs of chromosomes, each derived from one parent, are called homologous chromosomes .

8. Homologous Recombination General recombination or Homologous recombination ensures maintenance of genomic integrity. During meiosis, Homologous recombination results in DNA crossover events between homologous chromosomes that produce the genetic diversity inherent in germ cells. Accurate DNA replication and repair of DNA damage are essential to maintaining genetic information and ensuring its accurate transmission from parent to offspring. From the standpoint of evolution, it is also important to generate genetic diversity.

9. Crossing Over Crossing over is the exchange of genetic material between non-sister chromatids of homologous chromosomes during meiosis, which results in new allelic combinations in the daughter cells.

10. History and Discovery In early 1900s , William Bateson and Reginald Punnett found that certain genes associated with physical traits can be inherited together, or genetically linked. In 1911 , Thomas Hunt Morgan suggested that "crossovers" can occur between linked genes, where one of the linked genes physically crosses over to a different chromosome. In 1930s Barbara McClintock and Harriet Creighton demonstrated that chromosomal crossover occurs during meiosis Also in 1930s Curt Stern showed that crossing over—later called "recombination"—could also occur in somatic cells like white blood cells and skin cells that divide through mitosis.

11. Cont. In 1947 , the microbiologist Joshua Lederberg showed that bacteria are capable of genetic recombination, which is more similar to sexual reproduction. In 1964 Robin Holliday proposed a model for recombination in meiosis which introduced key details of how the process can work, including the exchange of material between chromosomes through Holliday junctions. In 1983, Jack Szostak and colleagues presented a model now known as the DSBR pathway , which accounted for observations not explained by the Holliday model. In 1990s experiments in Drosophila, budding yeast and mammalian cells led to the emergence of other models of homologous recombination, called SDSA pathways , which do not always rely on Holliday junctions.

12. Significance in Eukaryotes Homologous recombination is essential to cell division in eukaryotes like plants, animals, fungi and protists. In cells that divide through mitosis, homologous recombination repairs double-strand breaks in DNA caused by ionizing radiation or DNA-damaging chemicals. Left unrepaired, these double-strand breaks can cause large-scale rearrangement of chromosomes in somatic cells, which can in turn lead to cancer . Homologous recombination also helps produce genetic diversity through cross over between homologous chromosomes when cells divide in meiosis to become specialized gamete cells—sperm or egg cells in animals, pollen or ovules in plants, and spores in fungi. This creates new, possibly beneficial combinations of genes, which can give offspring an evolutionary advantage.

13. Cont. In Eukaryotes chromosomal crossover often begins when a protein called Spo11 makes a targeted double-strand break in DNA. These double-strand break sites often occur at recombination hotspots, regions in chromosomes that are about 1,000–2,000 base pairs in length and have high rates of recombination.

14. Significance in Bacteria Homologous recombination is a major DNA repair process in bacteria. It is also important for producing genetic diversity in bacterial populations, although the process differs substantially from meiotic recombination, which repairs DNA damages and brings about diversity in eukaryotic genomes. Homologous recombination has been studied in Escherichia coli in which two pathways were observed. Double-strand DNA breaks are repaired by the RecBCD pathway of homologous recombination. Breaks that occur on only one of the two DNA strands, known as single-strand gaps, are thought to be repaired by the RecF pathway .

15. Cont. Both the RecBCD and RecF pathways include a series of reactions known as branch migration (in which single DNA strands are exchanged between two intercrossed molecules of duplex DNA) and resolution (in which those two intercrossed molecules of DNA are cut apart and restored to their normal double-stranded state).

16. Significance in Viruses Homologous recombination occurs in several groups of viruses. In DNA viruses such as herpesvirus , recombination occurs through a break-and-rejoin mechanism like in bacteria and eukaryotes. There is also evidence for recombination in some RNA viruses, specifically positive-sense ssRNA viruses like retroviruses, picornaviruses , and coronaviruses. There is controversy over whether homologous recombination occurs in negative-sense ssRNA viruses like influenza.

17. Cont. Homologous recombination is important in facilitating viral evolution. It is the proposed mechanism whereby the DNA virus human herpesvirus-6 integrates into human telomeres.

18. Multiplicity Reactivation When two or more viruses, each containing lethal genomic damage, infect the same host cell, the virus genomes can often pair with each other and undergo homologous recombination repair to produce viable progeny. This is known as Multiplicity reactivation

19. Dysfunction in Homologous Recombination Without proper homologous recombination, chromosomes may incorrectly align for the first phase of cell division in meiosis. This causes failure to properly segregate resulting in nondisjunction . Nondisjunction can cause sperm and ova to have too few or too many chromosomes e.g. Down's syndrome.

20. Symptoms of Down’s syndrome

21. Cont. Deficiencies in homologous recombination have been strongly linked to cancer formation in humans. For example, each of the cancer-related diseases Bloom's syndrome, Werner's syndrome and Rothmund -Thomson syndrome are caused by malfunctioning copies of RecQ helicase genes involved in the regulation of homologous recombination

22. Cont. Decreased rates of homologous recombination cause inefficient DNA repair which can also lead to cancer eg . BRCA1 and BRCA2 , two similar tumor suppressor genes whose malfunctioning has been linked with considerably increased risk for breast and ovarian cancer.

23. Summary General recombination (also called homologous recombination) allows large sections of the DNA double helix to move from one chromosome to another, and it is responsible for the crossing-over of chromosomes that occurs during meiosis in fungi, animals, and plants. General recombination is essential for the maintenance of normal chromosome number in all cells.

24. References https://www.britannica.com/science/homologous-recombination https://en.wikipedia.org/wiki/Homologous_recombination Pierce BA. 2017. Genetics: A conceptual approach. W. H. Freeman & Cpmpany , USA, ISBN-10: 1319050964 Weaver, R. F., 2011 Molecular Biology 5 th ed., ISBN: 9780073525327

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