by:- Darshak Patel

:::MUTATION:::

DETAIL ABOUT MUTATION1)Defination:-dna & structure 2)Mutation:- A)Molecular B)chromosonal 3)Cause of mutation4)Types of mutation:- A)Somatic B)germ line a)effect of germ line mutation5)Control gene6)Sickle cell disease & Trait7)Role of Bioinformatics

What is DNA?

DNA or deoxyribonucleic acid is the hereditarymaterial in humans and almost all otherorganisms. Nearly every cell in a person’s bodyhas the same DNA. Most DNA is located in thecell nucleus (where it is called nuclear DNA), buta small amount of DNA can also be found in themitochondria (where it is calledmitochondrialDNA or mtDNA).

DNA is made of a long sequence of smaller units strung together. There are four basic types of unit: A, T, G, and C. These letters represents the type of base each unit carries: adenine, thymine, guanine, and cytosine. The sequence of these bases encodes instructions. Some parts of your DNA are control centers for turning genes on and off, some parts have no function, and some parts have a function that we don't understand yet. Other parts of DNA are genes that carry the instructions for making proteins — which are long chains of amino acids. These proteins help build a organism.

Protein-coding DNA can be divided into codons— sets of three bases that specify an amino acid or signal the end of the protein. Codons are identified by the bases that make them up — in the example at right, GCA, for guanine, cytosine, and adenine. The cellular machinery uses these instructions to assemble a string of corresponding amino acids (one amino acid for each three bases) that form a protein. The amino acid that corresponds to "GCA" is called alanine; there are twenty different amino acids synthesized this way in humans. "Stop" codons signify the end of the newly built protein.

After the protein is built based on the sequence of bases in the gene, the completed protein is released to do its job in the cell.

Central dogma of molecular biology

WHAT IS MUTATION A mutation is a change in DNA, the hereditary material of life. An

organism's DNA affects how it looks, how it behaves, and its physiology. So a change in an organism's DNA can cause changes in all aspects of its life.

Mutations are essential to evolution; they are the raw material of genetic variation. Without mutation, evolution could not occur.

Types of mutation

Molecular

Substitution Insertion Deletion Frameshift

Choromosonal

Inversion Duplication Translocation

Now we will look about

detail about mutation…

Substitution

A substitution is a mutation that exchanges one base for another (i.e., a change in a single "chemical letter" such as switching an A to a G). Such a substitution could:change a codon to one that encodes a different amino acid and cause a small change in the protein produced. For example,sickle cell anemia is caused by a substitution in the beta-hemoglobin gene, which alters a single amino acid in the protein produced.change a codon to one that encodes the same amino acid and causes no change in the protein produced. These are called silent mutations.change an amino-acid-coding codon to a single "stop" codon and cause an incomplete protein. This can have serious effects since the incomplete protein probably won't function.

InsertionInsertions are mutations inwhich extra base pairs areinserted into a new placein the DNA.

Deletion

Deletions are mutations inwhich a section of DNA islost, or deleted.

Frameshift• Since protein-coding DNA is divided into codons

three bases long, insertions and deletions can alter a gene so that its message is no longer correctly parsed. These changes are called frameshifts.For example, consider the sentence, "The fat cat sat." Each word represents a codon. If we delete the first letter and parse the sentence in the same way, it doesn't make sense.

• In frameshifts, a similar error occurs at the DNA level, causing the codons to be parsed incorrectly. This usually generates truncated proteins that are as useless as "hef atc ats at" is uninformative.

• There are other types of mutations as well, but this short list should give you an idea of the possibilities

Inversion

Chromosome segment breaks off Segment flips around backwards Segment reattaches

Duplication

Occurs when a gene sequence isRepeated.

Translocation

• Involves two chromosomes that aren’t homologous.• Part of one chromosome is transferred to another

chromosomes

The causes of mutations

1. DNA fails to copy accurately:- Most of the mutations that we think matter to evolution

are "naturally-occurring." For example, when a cell divides, it makes a copy of its DNA — and sometimes the copy is not quite perfect. That small difference from the original DNA sequence is a mutation.

2. External influences can create mutations:-

Mutations can also be caused by exposure to specific chemicals orradiation. These agents cause the DNA to break down. This is notnecessarily unnatural — even in the most isolated and pristineenvironments, DNA breaks down. Nevertheless, when the cell repairsthe DNA, it might not do a perfect job of the repair. So the cell wouldend up with DNA slightly different than the original DNA and hence,a mutation.

Types Mutations

1)Somatic mutation:-

Since all cells in our body contain DNA, thereAre lots of places for mutations to occur However , some mutations cannot be passedon to offspring and do not matter forevolution. Somatic mutations occur in non-reproductivecells and won't be passed onto offspring. Forexample, the golden color on half of this RedDelicious apple was caused by a somaticmutation. Its seeds will not carry themutation.

2)Germ line mutation:-

The only mutations that matter to large-scaleevolution are those that can be passed on tooffspring. These occur in reproductive cells likeeggs and sperm and are called germ linemutations

Effects of germ line mutations

1. No change occurs in phenotype2. Small change occurs in phenotype3. Big change occurs in phenotype

1)No change occurs in phenotype.Some mutations don't have any noticeable effect on the phenotype of an organism. This can happen in many situations: perhaps the mutation occurs in a stretch of DNA with no function, or perhaps the mutation occurs in a protein-coding region, but ends up not affecting the amino acid sequence of the protein.

2) Small change occurs in phenotype.A single mutation caused this cat's ears to curl

backwards slightly.

3)Big change occurs in phenotype.

Some really important phenotypic changes, like DDT resistancein insects are sometimes caused by single mutations. A singlemutation can also have strong negative effects for the organism.Mutations that cause the death of an organism are called lethals- and it doesn't get more negative than that.

CONTROL GENE

Little mutations with big effects: Mutations to control genes

Mutations are often the victims of bad press — unfairly stereotyped as unimportant or as acause of genetic disease. While many mutations do indeed have small or negative effects,another sort of mutation gets less airtime. Mutations to control genes can have major (and sometimes positive) effects.

Some regions of DNA control other genes, determining when and where other genes are turned"on". Mutations in these parts of the genome can substantially change the way the organism isbuilt. The difference between a mutation to a control gene and a mutation to a less powerfulgene is a bit like the difference between whispering an instruction to the trumpet player in anorchestra versus whispering it to the orchestra's conductor. The impact of changing theconductor's behavior is much bigger and more coordinated than changing the behavior of anindividual orchestra member. Similarly, a mutation in a gene "conductor" can cause a cascade ofeffects in the behavior of genes under its control.

Many organisms have powerful control genes that determine how the body is laid out. Example- Hox genes are found in many animals (including flies and humans) and designatewhere the head goes and which regions of the body grow appendages. Such master controlgenes help direct the building of body "units," such as segments, limbs, and eyes. So evolving amajor change in basic body layout may not be so unlikely; it may simply require achange in a Hox gene and the favor of natural selection.

Mutations to control genes can transform one body part into another. flies carrying Hox mutations that sprout legs on their foreheads instead of antennae!

Sickle cell trait&

Sickle cell disease(SCD)

A case study of the effects of mutation: Sickle cell anemia

Sickle cell anemia is a genetic disease with severe symptoms, including pain andanemia. The disease is caused by a mutated version of the gene that helps makehemoglobin —a protein that carries oxygen in red blood cells. People with two copiesof the sickle cell gene have the disease. People who carry only one copy of the sicklecell gene do not have the disease, but may pass the gene on to their children.

How Does a Child Get Sickle Cell DIsease?• Sickle cell disease is inherited through genes. Genes contain messages that

are passed on to the child through the mother's egg and the father's sperm. These messages control such qualities as eye color, blood type, and the kind of hemoglobin a person will have, etc.

• Germs do not cause sickle cell disease and you cannot catch it from another person like you catch a cold.

• For a child to have any form of sickling disease, each parent will have an abnormal hemoglobin. One possibility is that each parent has sickle cell trait (AS). Another possibility is when one parent has the disease (SS) and the other parent has sickle cell trait (AS).

• In hemoglobin SC disease, one parent has sickle cell trait and the other parent has a different trait (hemoglobin C). In sickle beta-thalassemia, one parent has sickle cell trait (or sickle cell anemia) and the other parent carries the trait for beta thalassemia (or has thalassemia major).

Where the mutation occur in Anemia

Official Gene Symbol: HBB

Name of Gene Product: hemoglobin, beta

Alternate Name of Gene Product: beta globin

Locus: 11p15.5 - The HBB gene is found in region 15.5 on the short (p) arm of human chromosome 11.

sickle-cell anemia is caused by a single point mutation in the nucleotide sequence of β-globin.

The mutation is located in the seventh codon (The first codon codes for Met, the leader aminoacid in polypeptides). The seventh triplet should read GAG which colds for glutamic acid, butthe middle nucleotide has changed to a thymine,which changes the triplet to GTG, which codes for valine.Replacement of the normally charged glutamic acid with the hydrophobic valine.

Replacement of the normally charged glutamic acidwith the hydrophobic valine alters the solubility of hemoglobin, so that at a lower oxygen concentration, the altered protein changes the red blood cell to a sickle shape that is unable to carry oxygen. This causes the symptoms of sickle-cell anemia.

There are effects at the DNA level

There are effects at the protein level

Normal hemoglobin (left) and hemoglobin in sickled red blood cells (right) look different; the mutation in the DNA slightly changes the shape of the hemoglobin molecule, allowing it to clump together.

Protein Function: Hemoglobin molecules, whichreside in red blood cells, are responsible forcarrying oxygen from the lungs to various parts ofthe body for use in respiration. The HBB genecodes for one of the two types of polypeptidechains found in adult hemoglobin. Normal adulthemoglobin is a tetrameric protein consisting of twoalpha chains and two beta chains. HBB codes for thebeta chain, which is often referred to as beta globin.Mutant beta globin is responsible for the sickling ofred blood cells seen in sickle cell anemia

There are effects at the cellular level>Normal red blood cells are round, soft, and flexible. Since they can squeeze through small blood vessels, blood flows easily.

>When red blood cells are shaped like a sickle, they are hard and rigid. These sickled cells can get stuck and plug up small blood vessels. The flow of blood and oxygen can be slowed down or stopped.

BIOINFORMATICS&

NCBI

How to get β-globin sequenceA. Focus on-actual nucleotide sequence for the β-

globin polypeptide.B. This sequence was obtained from GeneBank.C. KEY WORD: HUMHBBD. There are actually 73,308 nucleotides for

hemoglobin, which is located at the tip of Chromosome 11. This includes the β-globin gene as well as several other related globin genes .E. The sequence that contains the β -globin information is located between nucleotides

62,137 → 63,660.

62,137 - 63,660

Human β-globin sequence from 62137 → 6366062137 ACAT TTGCTTCTGA CACAACTGTG62161 TTCACTAGCA ACCTCAAACA GACACCATGG TGCACCTGAC TCCTGAGGAG AAGTCTGCCG62221 TTACTGCCCT GTGGGGCAAG GTGAACGTGG ATGAAGTTGG TGGTGAGGCC CTGGGCAGGT62281 TGGTATCAAG GTTACAAGAC AGGTTTAAGG AGACCAATAG AAACTGGGCA TGTGGAGACA62341 GAGAAGACTC TTGGGTTTCT GATAGGCACT GACTCTCTCT GCCTATTGGT CTATTTTCCC62401 ACCCTTAGGC TGCTGGTGGT CTACCCTTGG ACCCAGAGGT TCTTTGAGTC CTTTGGGGAT62461 CTGTCCACTC CTGATGCTGT TATGGGCAAC CCTAAGGTGA AGGCTCATGG CAAGAAAGTG62521 CTCGGTGCCT TTAGTGATGG CCTGGCTCAC CTGGACAACC TCAAGGGCAC CTTTGCCACA62581 CTGAGTGAGC TGCACTGTGA CAAGCTGCAC GTGGATCCTG AGAACTTCAG GGTGAGTCTA62641 TGGGACCCTT GATGTTTTCT TTCCCCTTCT TTTCTATGGT TAAGTTCATG TCATAGGAAG62701 GGGAGAAGTA ACAGGGTACA GTTTAGAATG GGAAACAGAC GAATGATTGC ATCAGTGTGG62761 AAGTCTCAGG ATCGTTTTAG TTTCTTTTAT TTGCTGTTCA TAACAATTGT TTTCTTTTGT62821 TTAATTCTTG CTTTCTTTTT TTTTCTTCTC CGCAATTTTT ACTATTATAC TTAATGCCTT62881 AACATTGTGT ATAACAAAAG GAAATATCTC TGAGATACAT TAAGTAACTT AAAAAAAAAC62941 TTTACACAGT CTGCCTAGTA CATTACTATT TGGAATATAT GTGTGCTTAT TTGCATATTC63001 ATAATCTCCC TACTTTATTT TCTTTTATTT TTAATTGATA CATAATCATT ATACATATTT63061 ATGGGTTAAA GTGTAATGTT TTAATATGTG TACACATATT GACCAAATCA GGGTAATTTT63121 GCATTTGTAA TTTTAAAAAA TGCTTTCTTC TTTTAATATA CTTTTTTGTT TATCTTATTT63181 CTAATACTTT CCCTAATCTC TTTCTTTCAG GGCAATAATG ATACAATGTA TCATGCCTCT63241 TTGCACCATT CTAAAGAATA ACAGTGATAA TTTCTGGGTT AAGGCAATAG CAATATTTCT63301 GCATATAAAT ATTTCTGCAT ATAAATTGTA ACTGATGTAA GAGGTTTCAT ATTGCTAATA63361 GCAGCTACAA TCCAGCTACC ATTCTGCTTT TATTTTATGG TTGGGATAAG GCTGGATTAT63421 TCTGAGTCCA AGCTAGGCCC TTTTGCTAAT CATGTTCATA CCTCTTATCT TCCTCCCACA63481 GCTCCTGGGC AACGTGCTGG TCTGTGTGCT GGCCCATCAC TTTGGCAAAG AATTCACCCC63541 ACCAGTGCAG GCTGCCTATC AGAAAGTGGT GGCTGGTGTG GCTAATGCCC TGGCCCACAA63601 GTATCACTAA GCTCGCTTTC TTGCTGTCCA ATTTCTATTA AAGGTTCCTT TGTTCCCTAA

There are 1,473 nucleotides in the gene, enough to code for 491 triplet codons. Butthe β-globin polypeptide has just 146 amino acids.The excess nucleotides are “introns”(intervening sequences) that separate the protein coding "exons“ (expressedsequences). The β-globin gene consists of three exons and two introns.

Exon #1 62187 – 62278 Intron #1 62279 – 62409

Exon #2 62410 – 62631 Intron #2 62632 – 63481

Exon #3 62482 – 63610

Open google

Type- NCBI goto EMBL-EBI

TOOLS SEQUENCE ANALYSIS

SELECT:- TRANSEQ

Sequence Translation is used to translate nucleic acid sequence to

corresponding peptide sequences.

1)Transeq (EMBOSS):-EMBOSS Transeq translates nucleic acid sequences to the corresponding peptide sequences.

2) Sixpack (EMBOSS):-EMBOSS Sixpack displays DNA sequences with 6-frame translation and ORFs.

Back-translation is used to predict the possible nucleic acid sequencethat a specified peptide sequence has originated from.

1) Backtranseq (EMBOSS):-EMBOSS Backtranseq back-translates protein sequences to nucleotide sequences.

2) Backtranambig (EMBOSS):-EMBOSS Backtranambig back-translates protein sequences to ambiguous nucleotide sequences.

Thank u……