# Presentation: 308208

## A Quest for Genes

- What’s a gene?

- gene (jēn)  *n.*
- A hereditary unit consisting of a sequence of DNA that occupies a specific location on a chromosome and determines a particular characteristic in an organism. Genes undergo mutation when their DNA sequence changes.
- [German Gen, from gen-, begetting, in Greek words (such as genos, race, offspring).]
- from: http://www.answers.com/topic/gene

**Genes** are the units of heredity in living _[organisms](http://en.wikipedia.org/wiki/Organisms)_. They are encoded in the organism's genetic material (usually _[DNA](http://en.wikipedia.org/wiki/DNA)_ or _[RNA](http://en.wikipedia.org/wiki/RNA)_), and control the development and behavior of the organism. The word "gene" ... is shared by many disciplines, including _[classical genetics](http://en.wikipedia.org/wiki/Classical_genetics)_, _[molecular genetics](http://en.wikipedia.org/wiki/Molecular_genetics)_, _[evolutionary biology](http://en.wikipedia.org/wiki/Evolutionary_biology)_ and _[population genetics](http://en.wikipedia.org/wiki/Population_genetics)_. Because each _[discipline](http://en.wikipedia.org/wiki/Discipline)_ models the _[biology](http://en.wikipedia.org/wiki/Biology)_ of _[life](http://en.wikipedia.org/wiki/Life)_ differently, the usage of the word gene varies between disciplines. It may refer to either material or conceptual entities.
- Following the discovery that _[DNA](http://en.wikipedia.org/wiki/DNA)_ is the genetic material, and with the growth of _[biotechnology](http://en.wikipedia.org/wiki/Biotechnology)_ and the project to _[sequence](http://en.wikipedia.org/wiki/Sequencing)_ the human _[genome](http://en.wikipedia.org/wiki/Genome)_, the common usage of the word "gene" has increasingly reflected its meaning in _[molecular biology](http://en.wikipedia.org/wiki/Molecular_biology)_, namely the segments of DNA which cells transcribe into RNA and translate, at least in part, into proteins. The Sequence Ontology project defines a gene as: "A locatable region of genomic sequence, corresponding to a unit of inheritance, which is associated with regulatory regions, transcribed regions and/or other functional sequence regions".
- From: http://en.wikipedia.org/wiki/Gene

## And so the gene is

- A segment of DNA
- It is **inherited**
- It is **transcribed**
- It may be **translated**
- It has regulatory and other functional regions

- it has certain **coordinates** and **sequence**

- genes in different organisms may be **homologous**

- its sequence may be **optimized for transcription**

- its sequence may be **optimized for translation**

- the **structure** and **sequence** of these regions may have something in common

**some/all of these features can be used to find genes**

## RNA- and protein-coding genes

- All genes are **transcribed**. Transcripts are messenger RNAs (**mRNA**s), ribosomal RNAs (**rRNA**s), transfer RNAs (**tRNA**s), etc.
- Only **mRNAs** are **translated** into proteins

## Protein-coding genes

- are **transcribed and translated**
- their sequence is **optimized** for **transcription** and **translation**

## Transcription

- Is performed by a special enzyme – **RNA polymerase**
- RNA polymerase binds strongly to a specific **promoter** sequence, where DNA is **unwound**
- RNA is polymerized in 5’>3’ direction (DNA is read from 3’>5’)
- RNA polymerization is stopped upon reaching a **terminator**

**Signals in DNA** sequence that can be recognized: **promoters**  and **terminators**. Promoters are A+T rich for easy strand separation, terminators are G+C rich.

**Most important contribution: transcription-coupled DNA repair **

## Transcription-coupled DNA repair and mutational drift

- Mutations: **transitions** (purine to purine or pyrimidine to pyrimidine) and **transversions** (purine to pyrimidine or pyrimidine to purine)
**Transitions** are **more common** than transversions
**Transitions** change **G:C to A:T** or **C:G to T:A**
- If **unrepaired**, spontaneous mutations will **enrich DNA** **sequence with A+T,** while G+C will disappear

- Sequences **repaired more efficiently** will have **higher G+C** content than the rest of the genome
- The **rate-limiting step** in DNA repair is **recognition** of damaged base pairs
- Damaged base pairs are efficiently **recognized by RNA polymerase**, which stalls and attracts DNA repair machinery
**Actively transcribed** sequences are **repaired more efficiently** than the rest of the genome

**Protein-coding regions will have higher G+C content than non-coding regions**

## Translation

- Ribosome binds to a region upstream of the **start codon** (**Shine-Dalgarno sequence**)
- The **start codon** defines the **reading frame** for subsequent codons
- mRNA is read in 5’>3’ direction
- Translation is **terminated** upon reaching a **stop codon**

- Signals in DNA sequence that can be recognized:
- Shine-Dalgarno
- start codons (AUG, GUG, UUG)
- stop codons (UAG, UGA, UAA)
- open reading frames (ORFs)
-  codon, di-codon and tri-codon usage
- amino acid composition

## Computational protein-coding gene prediction algorithms

- Find a set of **ORFs**
- Consider some ORFs as “**typical protein-coding sequences**” and some other regions as “**typical non-coding sequences**” for use as a **training set**
- Find some **features** that would distinguish “**typical coding** sequences” from “**typical non-coding** sequences” (GC content, codon usage, di-codon usage, patterns, motifs, etc.)
- Find other ORFs with **similar features**

- GeneMark
- Glimmer
- GeneScan
- GeneLook
- GeneHacker
- EasyGene
- GS-Finder
- ZCurve
- Orpheus
- Fgenes
- Critica
- ...

**How typical is your “typical **
**coding” sequence?**

## Guinness Book of protein-coding genes

- The **longest** human gene is **2,220,223** nucleotides long. It has 79 exons, with a total of only 11,058 nucleotides, which specify the sequence of the **3,685** amino acids and codes for a protein dystrophin. It is part of a protein complex located in the cell membrane, which transfers the force generated by the actin-myosin structure inside the muscle fiber to the entire fiber.
- The **smallest** human gene is **252** nucleotides long, it specifies a polypeptide of **67** amino acids and codes for an insulin-like growth factor II.

- The **longest** bacterial gene is **110,418** nucleotides long, which specify the sequence of **36,805** amino acids. Its function is unknown, most likely a surface protein.
- The **smallest** bacterial gene is **54** nucleotides long, it specifies a polypeptide of **17** amino acids and codes for a regulatory protein in cyanobacteria

## Computational protein-coding gene prediction algorithms identify correctely 90-95% of genes.

- Manual analysis is required to find the rest.