Gene Linkage

 GENE LINKAGE

According to the chromosome theory of inheritance, units of heredity called genes reside on the chromosomes. The number of genes in a cell is greater than the number of chromosomes. Human beings for example have 46 chromosomes and thousands of genes. Therefore, each chromosome has hundreds and thousands of genes. Such genes tend to inherit together exhibiting gene linkage.  Gene linkage is the phenomenon in which the genes on the same chromosome stay together and tend to inherit together. This phenomenon was first explained in 1910 by Thomas H. Morgan and his student, Alfred H. Sturtevant while working on Drosophila.

 

Linked genes

Genes that are located on the same chromosome and tend to be inherited together in genetic crosses are said to be linked genes. The linked genes are not free to undergo independent assortment. These genes can only segregate if crossing over occurs during the gametogenesis. The crossing-over event results in the reshuffling, or recombination, of the alleles between homologs. This results in the formation of recombinants. The frequency with which crossing over occurs between any two linked genes is generally proportional to the distance separating the respective loci along the chromosome.

 

Linkage group

A linkage group refers to all the genes located on a single chromosome that are inherited together as a unit. The number of linkage groups should correspond to the haploid number of chromosomes. In humans, the number of linkage groups corresponds to the number of chromosome pairs, which is 23 (or 24 in males, due to the X and Y chromosomes).

 

 

Autosomal linkage and Sex linkage

The gene linkage phenomenon occurs on both autosomes and sex chromosomes. When a group of genes are linked together on an autosome it is called autosomal linkage. When genes are linked on a sex chromosome, their linkage is called sex linkage. In human beings, the genes for sickle cell anemia, leukemia, and albinism are found on chromosome 11. Thus these genes are linked genes and the type of linkage is autosomal linkage. These genes tend to be inherited together in the offspring.

 

22.6.2 Detection of gene linkage

A dihybrid test cross (between two gene pairs) can detect gene linkage. In a dihybrid test cross, a heterozygous individual for two traits is crossed with a recessive parent for two traits. If only parental variety is produced then a tight linkage exists between the genes for the two traits. When both parental and recombinants (four phenotypic combinations) are produced in equal 1:1:1:1 ratio, then there would be no linkage between the genes. When this ratio is deviated i.e. more parental types and less recombinant types, this indicates incomplete or partial linkage.

 

T. H. Morgan performed a dihybrid test cross to see how the linkage between genes affects the inheritance of two different characters in Drosophila. In Drosophila, the normal shape of wings is dominant over the vestigial wing. Similarly, grey body color is dominant over black body color.

 

Character	Dominant trait	Recessive trait
Wing shape	Normal wing	Vestigial wing
Body color	Grey color	Black color

 

Morgan made a cross between the individual having a grey body and normal wings with another individual having a black body and vestigial wings, all the F1 progeny inherited grey bodies and normal wing phenotypes, When F1 flies were test crossed with their P1 recessive, following results were observed:

a.      Grey body and normal wings (parental type) = 965

b.     Black body and vestigial wings (parental types) =944

c.      Grey body and vestigial wings (recombinant types) =206

d.     Black body and normal wings (recombinant types) =185

From the above parental and recombinant ratio, Morgan concluded that the genes for body color and wing size are located on the same chromosome (linkage exists). However, a small number of recombinants indicated that occasionally this linkage breaks (due to crossing over).

 

Crossing over breaks gene linkage

Crossing over is an exchange of maternal and paternal chromatid parts between homologous chromosomes. This exchange of chromosomal segments occurs during the prophase of meiosis I. This recombination brings alleles together in new combinations, resulting in a variety of gametes. Crossing over results in the breaking of gene linkage and the formation of recombinants. The farther apart two genes are, the higher the probability that a crossover will occur and therefore the higher the recombination frequency.

Linkage and Mendel’s laws

Mendel's laws do not follow gene linkage. Gene linkage is an exception to Mendel’s second law (the Law of Independent Assortment). Mendel’s Law of Independent Assortment assumes that genes are located on different chromosomes or are far apart on the same chromosome, so they assort independently during meiosis. Gene linkage happens when genes are close together on the same chromosome, so they are often inherited together. This means they do not assort independently.

 

 

Gene

 

In 1877, Johannsen coined the term gene. A gene is a short segment of DNA having a specific nucleotide sequence that codes for a polypeptide chain. Number of genes is variable in different organisms. The following table shows the amount of DNA, haploid number of chromosomes, and number of genes of some organisms.

Structure and organization of genes:

All organisms have genetic material in the form of DNA or RNA. Some of the sequences code for a polypeptide chain and are called coding sequences (genes) the other do not code for any polypeptide and are called non-coding sequences (Junk DNA). These no-coding sequences are found interspersed in the genetic material. In prokaryotes, almost all the non-coding DNA is found between genes as intergenic DNA. In eukaryotes, non-coding DNA is scattered throughout the eukaryotic chromosomes. It is present between the genes and also in the actual genes. These non-coding sequences in the genes are known as introns,

 

The structure of a typical eukaryotic gene can be represented by the human β-globin gene, This gene consists of the following elements:

 

a.      Promoter

 

A promoter region is responsible for the binding of RNA polymerase and the initiation of transcription. The promoter region of the human β-globin gene has three distinct units and extends from 95 to 26 base pairs before ("upstream from") the transcription initiation site (i.e., from -95 to -26). The promoters in prokaryotes are TATAAT (Pribnow box )and TTGACA located at -10 and -35 respectively in eukaryotes they are TATA and CAAT located at -25 and -70.

 

b.      Transcription initiation site

 

The transcription initiation site is the region from where the RNA polymerase enzyme starts the synthesis of RNA molecules. This site for human β-globin is ACATTTG. This site is often called the cap sequence because it represents the 5´ end of the RNA, which will receive a "cap" of modified nucleotides soon after it is transcribed.

 

c.      Translation initiation site

 

The translation initiation site, ATG. This codon (which becomes AUG in the mRNA) is
located 50 base pairs after the transcription initiation site in the human β-globin gene (although
This distance differs greatly among different genes).  The intervening sequence of 50 base pairs between the initiation points of transcription and translation is the 5´ untranslated region, often called the 5´ UTR or leader sequence.

 

d.     Exons and introns    

 

The regions of the DNA that contain coding information are known as exons. Exons have intervening sequences that do not code for any amino acid known as introns. Intron Segment of a gene that does not code for protein but is transcribed and forms part of the primary transcript. Exon is the Segment of a gene that codes for protein and that is still present in the messenger RNA after splicing.

 

·       β-globin gene the first exon, contains 90 base pairs coding for amino acids 1 30. ·       An intron containing 130 base pairs with no coding sequences for the globin protein. ·       An exon containing 222 base pairs coding for amino acids 31 104. ·       A large intron 850 base pair has nothing to do with the globin protein structure. ·       An exon containing 126 base pairs coding for amino acids 105 146

 

e.      Translation termination codon

 

A translation termination codon, TAA. This codon becomes UAA in the mRNA. The ribosome dissociates at this codon, and the protein is released.

 

f.       3´ untranslated region

 

A 3´ untranslated region that, (3´ UTR) although transcribed, is not translated into protein.
This region includes the sequence AATAAA, which is needed for Polyadenylation. The poly(A) tail is inserted into the RNA about 20 bases downstream of the AAUAAA sequence.

Gene and chromosome differences

Chromosomes are thread-like structures composed of DNA and proteins. These are present inside the nucleus of every cell of an organism. The DNA consists of many Specific segments of DNA that can synthesize proteins called genes.  Genes, therefore, are composed of specific nucleotide sequences. All genes instruct the cell to make certain proteins. The location of a gene on a chromosome is called locus.

Chromosomes

 Chromosomes are the structures within living cells that contain the genetic material. Its primary function is to store the information needed to produce the characteristics of an organism. Chromosomes are a condensed form of DNA. Each chromosome is composed of only one long DNA molecule. A eukaryotic chromosome is composed of DNA and proteins. A typical chromosome is composed of a few million base pairs (bp). For example, the chromosome of Escherichia coli has approximately 4.6 million bps.

Eukaryotes have chromosomes inside their nucleus and in a bacterial cell, a chromosome is highly compacted and found within a region of the cytoplasm known as a nucleoid. Chromosomes were discovered by Walther Flemming in 1876. The term chromosome was coined by Weldeyer in 1888.

Structure of chromosomes

In a eukaryotic cell, chromosomes are composed of a single molecule of DNA and five types of histone proteins. Histone molecules are rich in lysine and arginine residues. These proteins are positively charged and, therefore,  bind tightly to the negatively charged phosphates in the DNA molecule.  A small portion of non-histone proteins are also present. These proteins regulate transcription, thus called Transcription factors. 

During most of the cell’s life cycle, chromosomes are elongated fibers and cannot be observed under the microscope. In this state, it is active and able to duplicate and transcribe.  These fibers begin to condense at the beginning of cell division which can be stained and observed easily under the light microscope. These condensed chromosomes also have their duplicated copy and are known as dyads. A chromosome has the following components.

1. Chromatids

During the S phase of the cell cycle, the chromosomes are duplicated. These chromosomes when condensed during division form two arms called chromatids. The duplicated chromosomes are held together at the region of centromeres. The attached, duplicated chromosomes are commonly called sister chromatids. The shorter arm of the two arms of the chromosome extending from the centromere is called the p arm and the longer arm is known as the q arm.

2. Centromere

Centromeres are regions that attach the duplicated chromosomes. It plays a role in the proper segregation of chromosomes during mitosis and meiosis. Most of the eukaryotic chromosome contains a single centromere. The centromeres act as a site for the formation of kinetochores that link the centromere to the spindle apparatus during mitosis and meiosis. The length of the DNA in centromere can range in length from several thousand base pairs to over 1 million bp. Some chromosomes also have a satellite and a secondary constriction (nucleolar organizer). The satellites are knobs and have no known function it is considered junk DNA

            c.      Telomeres

Telomeres are the specialized regions found At the ends of linear chromosomes. These have important functions in the replication and structural stability of the chromosome. Telomeres prevent translocations and chromosome shortening. It also protects chromosomes from digestion by exonucleases.

Classification of chromosomes

Chromosomes are classified on the following basis.

A.     Autosomes and Sex Chromosomes

Human beings have 23 pairs of chromosomes in their cells. These chromosomes are of two types; autosomes and sex chromosomes. Sex chromosomes include the X and Y chromosomes. The other 22 pairs of chromosomes are autosomes. Characters that are linked to the sex of the person are passed on through the sex chromosomes. The rest of the genetic information is present in the autosomes.

B.      Based on the Number of Centromeres

Chromosomes are also classified based on the number of centromeres. Monocentric chromosomes have one centromere, Dicentric have two centromeres, and Polycentric have more than two centromeres. Chromosomes without centromere are called Acentric chromosome fragments.

C.      On the Basis of Location of Centromere

Chromosomes have the following types based on the position of their centromere.

i.       Metacentric chromosome; the chromosomes with the centromere at the center. These chromosomes have equal arms.

ii.     Sub-metacentric chromosome; the chromosomes with the centromere closer to one end. These chromosomes have unequal arms, the shorter arm is called as p arm, and the longer arm is called the q arm.

iii.   Acrocentric chromosome; the chromosomes with the centromere are too close to the one end. This chromosome also has a secondary constriction called the nucleolar organizer.

                   iv. Telocentric chromosome; the chromosomes with the centromere at one side.

Number of chromosomes

 

The number of chromosomes is variable in different species. Each species has its specific number of chromosomes. Organisms with only one set of chromosomes are called Monoploid, with two sets of chromosomes called Diploid, with three sets called Triploid, with four sets called Tetraploid, and with six sets of chromosomes are called Hexaploid. The term Haploid usually refers to half of the somatic chromosome number. A haploid number of chromosomes may be diploid or triploid.

The haploid chromosome numbers of a few representative species are given in the table below.

Chemical composition of chromosomes

A eukaryotic chromosome is chemically composed of 60% proteins and 40% DNA. Each chromosome is composed of a single molecule of DNA and five types of histone proteins. These are H₂A, H₂B, H_3, H₄ and H_1. Histone molecules are rich in basic amino acids lysine and arginine residues.

Fine structure of chromosomes

A chromosome has three levels of organization.

1. The first level of organization;

Each chromosome is chemically composed of DNA and basic proteins. The DNA and histone proteins when combined are referred to as nucleosomes. Two molecules of each histone protein H₂A, H₂B, H_3, and H₄ combine to form an octamer called histone Core Particle. Around the histone Core Particle DNA coils for two turns forming nucleosomes. The nucleosome is bead bead-like structure that is 10nm in thickness.

The DNA that coils around the histone core is called core DNA. Core DNA is 146 base pairs in length. A short sequence of nucleotides extends between two nucleosomes called Linker DNA. The length of linker DNA is variable and ranges from 8-114 base pairs.

The H₁ binds the linker DNA to the nucleosome where it enters the nucleosome and leaves the nucleosome.

1. Secondary level of organization:

The second level of organization is a 30nm thick fiber called solenoid. The H₁ binds the two nucleosomes forming loops with six nucleosomes in a turn called Solenoid.

2. The final level of organization:

The final level of organization is a 700nm thick structure called a chromosome. It is the result of condensation by coiling and supercoiling of solenoid. The densely packed chromatin is called heterochromatin and appears as dark regions. The loosely packed chromatin is called the Euchromatin. It appears as light regions.

23.1.4 Karyotype:

A karyotype is a chromosomal chart of an organism that displays the chromosomes of an organism arranged into pairs. A karyotype shows the number of chromosomes of an organism, their shapes, and sizes. Every species has a characteristic karyotype.

There are 46 chromosomes in a human somatic cell arranged in 23 pairs. 22 pairs of these are called autosomes and one pair is a sex chromosome that determines the sex of an organism.

A normal karyotype is shown in Fig below.