1. Genomes and Genomics

2. Learning Objectives By the end of this class you should understand:
The information that may result from sequencing a genome
The techniques and purpose of genetic maps
The history of sequencing the human genome and its future potential
The primary study and tools of the field of bioinformatics
The relationship between the genome and the proteome and exome
Concerns about ownership and genomes

3. Advancing Genetic Knowledge
Mutations have always been a major foundation for understanding genetics
Without mutations we would all be identical!
Before genetic sequencing, before even DNA, mutations were used to track relationship between genes

4. Chromosomal Linkage
A chromosome with two defects will create both-or- neither inheritance
Recall this is chromosomal linkage
All genes on X chromosome are linked
Hemophilia and colorblindness showed linkage
Autosomal linkage took much longer to find

5. Chromosomal Linkage
Nail-Patella Syndrome and Blood Type were finally linked
We now know they are both on chromosome 9
However, linkage was not total
Remember crossing over? AKA Chromosomal recombination

6. Crossing Over
Recall during meiosis (Prophase I) chromosomes will exchange DNA
This enables us to track what genes are on what chromosome
And where!

7. Chromosomal Linkage

8. Chromosomal Distance
The closer two genes are on a chromosome, the more frequently they will cross over together
The farther away they are, the more one will recombine without the other
Percentage of recombination measured in units of centimorgans
2/16 = 12.5% = 12.5 centimorgans distance

9. Genetic Cloning
Thanks to PCR and improved DNA sequencing, many genes were mapped to chromosomes starting in the 1980s
Huntington's, Cystic Fibrosis, Retinoblastoma, etc
The Human Genome Project was initiated in 1990

10. Human Genome Project Goal: Seq uence entirety of human genome
Additional goal: figure out what genes do what
Additional goal: sequence other animals/plants
Work got faster and faster as time went on
Computers were created that could accelerate the project

11. DNA Sequencing Human genome is 3.2 billion DNA bases
Not the largest, not even close!
Marbled lungfish genome: billion DNA bases
That is NOT a typo!
Sequencing entire genome took a long time!

12. History of Human Genome Project

13. Sequencing Methods
Map-based sequencing locates sequences of DNA relative to markers found on each chromosome
A comprehensive map of which genes are on which chromosome can be constructed and measured in centimorgans
Whole genome sequencing slices the entire genome into cloned libraries then sequences them all using computer technology

14. Sequencing Methods

15. Genome Sequencing
Entirety of genome can now be sequenced in days instead of years
Still expensive but getting cheaper!
The human genome is 98% noncoding
The coding portion of the human genome is called the exome

16. Genome vs. Exome Exome is the coding portions of DNA only
Codes for proteins
A scan of all exons in genome
50 times less data to analyze
Used to screen and diagnose for genetic disorders
May not catch CNV disorders

17. Now What? Once you have a genome, what do you do with it?
The field of bioinformatics addresses what to do with this massive amount of data
Bioinformaticians must be skilled in computer science and math (linear algebra and probability)

18. Bioinformatics Specialties
Comparative Genomics
Studying relationship between different animals/plants/bacteria
Structural Genomics
Studying structure of proteins produced by genes
Pharmacogenomics
How to make drugs to repair diseases

19. Bioinformatics Basics
The most important skill in bioinformatics: locating a gene!
Find the gene in the following sequence:
ACAGGAGAAATATACCAATACCGCTTGCGAGAGATCATGGAATCTCGAGCGTTATGTGAATGCTGAAAAAAAAAAA
A bioinformatician can find it!
Technically the entire sequence is a gene but the bioinformatician can find the start codon and the upstream promoter region
Technically the bioinformatician can write a computer program to do that for him/her

20. Gene Location
By homing in on clues like the TATA box and CCAAT initiator sequence, bioinformaticians can locate genes
This is known as annotation
Must be compared to protein sequences to have introns identified

21. Annotation

22. Introns and Exons
The codons (beginning with ATG) form an open reading frame (ORF)
The origin of the term frameshift
Insertion/deletion mutations may alter the frameshift unless they occur in an intron
Intron variability is much higher than exons!
Computers can detect all these predictable patterns

23. Genes in Genome

24. Full Genome
Remember that standard genes comprise only 2% of the genome, tops
Long stretches of DNA are repeated sequences that still serve important functions!
Alterations to these repeated stretches in one spot are called single nucleotide polymorphisms

25. “Junk” DNA Alterations
Single base changes (SNPs) can be compiled into a haplotype
Similar to a bar code of the chromosome
Reveals where the chromosome was inherited from and who else have a closely related chromosome
Changes to the number of repeated bases are called copy number variants

26. Copy Number Variants CNVs alter the length of a chromosome
Since DNA can affect expression of genes thousands of bases away, CNVs are linked to various disorders
Probably due to variable or reduced expression of the associated gene/protein

27. Genome vs. Proteome
Even though there are only 25,000 genes, there are over 200,000 proteins
Possibly up to a million!!
Due to differential intron/exon splicing
All the proteins in the body together make the proteome
Studying proteins is called proteomics

28. Concerns of Genomics Major concern: who owns your genome?
Remember, now genes CANNOT be patented
Research still belongs to company even if it's done with your tissue
Major concern: should we be testing genomes of healthy people?
Especially while information is incomplete!

29. Happy Wednesday!