Genetics 101

From cell to organ

Cells are the basic building blocks of our body. Many similar cells grouping together form tissue to perform a specialized function, and a group of tissues working together form an organ for a common purpose. Two or more different organs further make up an organ system to provide a particular function. Digestive system, for example, is composed of several organs including mouth, stomach, liver, and intestines. Liver, made up of hepatic tissue, connective tissue, and nerve tissue, has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion.  Sixty percent of the liver is hepatic tissue, which contains millions of hepatic cells.

Components of the cell

Now let’s take a close look at cells. Our body contains a total of 50 trillion cells, with size ranging from 4 to 100 micrometers (one-thousandth of a millimeter). Each cell is a membrane-bounded compartment filled with a concentrated water solution of chemicals. Broadly speaking, the building blocks of a cell are just four major families of small organic chemicals: sugars, fatty acids, amino acids, and nucleotides. Sugars provide energy to the cell. Fatty acids make up the cell membranes, separating the cells from the environment, and further forming compartments within the cell. Amino acids are the subunits of proteins, which constitute more than half of the dry weight of the cell. Proteins determine the shape and structure of the cell and also serve as the catalysts of almost all chemical reactions in the cell. Twenty amino acids, each with a distinct personality, form many many different proteins through assortment and folding, to carry out many many different functions.

Gene

So what determines the amino acid sequence of a particular protein?  It’s the gene, a sequence of nucleic acids composed of nucleotide subunits. There are two types of nucleic acids, DNA (deoxyribonucleic acid) and RNA (ribonucleic acid), which differ in the structure of the sugar in their nucleotides (DNA contains deoxyribose while RNA contains ribose). Nucleotide consists of three components: a nucleobase, a sugar, and a phosphate group. Nucleobase adenine (A), cytosine (C), and guanine (G) are found in both RNA and DNA, whereas thymine (T) occurs in DNA and uracil (U) occurs in RNA. Most DNAs exist as a double-stranded structure where 'A' on one chain always pairs with 'T' on the other, and 'C' always pairs with 'G'. This 'complementarity' is key to the replication process when DNA molecules in the parental cells are passed to the offspring cells. The sum total of all our DNA sequences is called genome. It is like a huge tome written in letters of A/T/C/G. Some pages of the tome are blueprints for proteins (human beings have 20,000 - 25,000 protein genes), some pages have instructions on how to make different proteins, some pages may have messages telling the cell where to begin making new DNA, yet 97% of those pages are not understood so far!

From gene to protein

The process of producing a biologically functional molecule of either protein or RNA is called gene expression, and the resulting molecule itself is called a gene product. Those genes that code for proteins are composed of tri-nucleotide units called codons, each coding for a single amino acid. There are 20 natural amino acids, and a code of 3 nucleotides could code for a maximum of 64 amino acids, so some different codons represent the same amino acid. Protein-coding sequences comprise less than 1.5% of the human genome. Aside from known protein genes and regulatory genes, 97% of the human genome contains vast regions of DNA the function of which, if any, remains unknown. For protein genes, the DNA sequence is first transcribed to messenger RNA (mRNA), and then translated from mRNA to protein.

Chromosome

The whole human genome contains more than 3 billion DNA base pairs, and the entire DNA from a single human cell can expand 3 meters long if connected head to tail. How does a 0.05-mm cell store so much DNA? This is done by some incredible winding process to compact DNAs together with some proteins into complex bundles called chromosomes. All of our genetic information are stored in 23 pairs of chromosomes, 23 from our mother and the other 23 from our father. One pair is sex-determining, while the remaining 22 pairs are called autosomes. The paired autosomes are almost identical in size and content, whereas the sex chromosomes, X and Y chromosomes are very different because they carry the genes responsible for sex determination. If you inherited an X chromosome from both mother and father, you are female; if you inherited an X chromosome from your mother and a Y chromosome from your father, then you are male.

Ovum and sperm, so-called gamete, contains one half of the chromosomes from our mother and one half of the chromosomes from our father, respectively. Which chromosome they get from each pair is random, making every gamete unique. When the gametes are produced, each pair of chromosomes makes contact and exchanges pieces of DNA, then the resulting hybrid chromosomes are separated and sorted into individual gamete. This process is called recombination, making any chromosome you inherited from your mother essentially a mosaic of chromosomes she inherited from her parents. So are the chromosomes you inherited from your father. This shuffling increases the variability of characteristics among individuals.

SNP

We all began existence as a single cell, generated by fusion of an ovum and a sperm. The fused cell (fertilized egg) divides into two and two divide into four, thus generate and differentiate into billions of cells. Because of the strictly regulated replication process, every cell of our body (so-called somatic cell) contains the same set of DNA molecules, except that the gamete only contains one half of the DNA content. But, why are there different kinds of cells with different shape and function? Because certain genes are expressed in certain kind of cells at certain times but not in others.

Although the DNA replication is of extremely high fidelity, cells do make mistakes sometimes during the copying process, just like typos. Some typos are lethal and get eliminated quickly. Some are not lethal but instead lead to new traits such as appearance, disease susceptibility or response to drugs. Such typos are important for evolution. Some typos make no difference to the translated amino acid sequence - remember some different codons represent the same amino acid - thus are kept, too. These variations in the DNA sequence at particular locations are called single nucleotide polymorphisms (SNPs, pronounced "snips").

As you already know, our every single cell, except for sperm and ovum, carries 46 chromosomes, 23 from our mother and the other 23 from our father. This means that for any nucleotide located on an autosomal chromosome we have inherited two versions (one maternal and the other paternal). These are usually referred to as two alleles for that particular location in the genome. For example, a C allele from mother but a T allele from father at a particular location. At a larger scale, correspondingly, each gene has one copy (and therefore one allele) on each chromosome. For 99.9% locations in the chromosome pairs, we have inherited the same allele, the other 0.1%, which translates into millions of locations, are different because of SNPs. If you were to compare your DNA sequence with that of John, your neighbor, you would expect to find averagely one SNP that differs every thousand nucleotides. The number of SNPs where you match another person can therefore be used to tell how closely related you are.