One of the gene kingdoms: the long-awaited "C position big shot" - gene

Produced by: Science Popularization China

Author: Li Lei

Producer: China Science Expo

In the prologue, we introduced the initial exploration of genetic material. Several scientists proved through three experiments that nucleic acid is genetic material. Mendel, a genius, also directly proposed the existence of genetic factors and gave research on the laws of genetics.

So, are genetic material and genes the same thing? What is our understanding of genes? Today we will talk about genes.

Genes—the core of genetic material

Now that we understand that nucleic acid is genetic material, we can return to our original question: what is a gene?

Based on simple biochemistry knowledge, we know that the basic composition of nucleic acids is very simple, which is four nucleotides, namely adenine (A), guanine (G), thymine (T) and cytosine (C). The combination of these four forms our genetic material DNA.

Nucleotides

(Image source: wiki)

The nitrogen-containing compounds that form nucleosides are called bases, which can be divided into four types: ATGC based on their specific differences. Next is the structure composed of sugar and phosphate groups, which is exactly the same in DNA, except that they are divided into deoxyribose (DNA backbone) and ribose (RNA backbone) based on the difference in oxygen on the sugar.

However, another question arises: what is the combination of these A, T, G, and C, and what is their significance? Are they random combinations or are they regular? How are their specific information converted into the traits we observe? What parts of DNA are related to the differences between different life forms?

It's like there is an English book in front of you. You know it must be written with 26 letters such as ABCDE, but you have no idea what the specific content of the book is.

To solve the problem, we must open this book and understand what the A\T\G\C sequence of DNA is like.

A, T, C, G

(Image source: Arizona State University)

This triggered the scientific exploration of the structure of DNA . Of course, this problem cannot be solved all at once, but must be carried out step by step.

First, we need to figure out what the overall structure of DNA is like.

However, this is not easy. At that time, we did not have more sophisticated means of observation and could only rely on speculation. As a result, there were many theories. For example, someone proposed the "tetranucleotide hypothesis" that DNA is composed of four equal amounts of nucleotides.

It was not until 1950 that Chargev first determined that the number of A and T bases in DNA is the same, and the number of G and C is the same. This rule laid the foundation for the basic principle of complementary base pairing in DNA structure, that is, A=T, C=G.

With this principle in mind, scientists Wilkins and Franklin began to use X-ray diffraction to analyze the structure of DNA crystals. Through continuous trial and improvement, they successfully took clear DNA diffraction photos, which is the famous picture below.

DNA diffraction pattern

(Image source: wiki)

It was after seeing this picture that young Watson and Crick jointly proposed a hypothesis about the structure of DNA, which is a double helix. Simply put, DNA is a structure composed of two chains, each of which is composed of ATGC, but they are not completely isolated, but each position of the two chains is complementary, that is, A=T, G=C, which forms a stable double helix structure.

Watson and Crick

(Image source: wiki)

This discovery was truly groundbreaking. It took only 23 days from submission to publication in Nature, almost setting a record. The three discoverers, Wilkins, Watson, and Crick, soon won the Nobel Prize together. This discovery was later listed as one of the three great discoveries in natural science in the 20th century, along with relativity and quantum mechanics, which shows its importance.

Of course, there is a bit of regret that Franklin, who took that crucial photo, did not win the Nobel Prize because she died of cancer in 1958, and this discovery was not awarded the Nobel Prize until 1962.

The DNA double helix model not only allows us to find the structure of DNA, but also means that we have found the DNA replication mechanism. As long as we know the information of one of the DNA chains, we can get the information of the other chain. This is the charm of base complementary pairing. The process of DNA replication itself is to retain the information of one chain and then synthesize the other chain through base complementary pairing. This is semi-conservative replication. This also provides a basis for us to further interpret DNA, so the second question naturally arises.

We have to consider what the DNA sequence looks like?

To understand the specific situation of the DNA sequence, that is, the arrangement of ATGC on the DNA, it is necessary to test it. This practice has a special term in biology called sequencing.

Of course, since DNA itself is a nucleotide, scientists thought of using chemical methods to react and detect which nucleotide it is.

The famous biologist Sanger creatively found a strategy. He used a special nucleotide - dideoxynucleotide . The full name of RNA is ribonucleotide. Compared with RNA nucleotides, DNA nucleotides have one oxygen removed, so they are called deoxyribonucleotides. This dideoxynucleotide has one more oxygen removed than DNA. This makes its chemical properties a bit special. That is, when the DNA polymerase moves to this position, it cannot continue because there is one less oxygen in the dideoxynucleotide structure, and it can only terminate. In this way, we can judge what kind of deoxynucleotide is at this position based on the instructions of the dideoxynucleotide.

DNA Sequencing Process

(Image source: wiki)

The invention of this method directly solved the problem of DNA sequencing, so it is called the first generation sequencing method. RNA sequencing also needs to convert it into DNA and then be sequenced according to DNA. The invention of the first generation sequencing also laid the foundation for the development of the human genome project, which we will talk about later. By the way, Sanger not only sequenced DNA, but also sequenced proteins, which won him two Nobel Prizes.

With the emergence of sequencing technology, we have officially opened up the world of genes, and will usher in rapid development of life sciences, especially molecular biology and genetics.

Only now can we formally discuss the main topic - genes.

Genes and genomes

After DNA sequencing was realized, we finally knew the arrangement of ATGC on DNA, that is, the sequence, and for the first time saw the world of genes in its entirety. It turns out that whether it is Chinese or foreigners, whether it is animals or plants, or even viruses, what really determines various traits is a long ATGC arrangement. This arrangement has both differences in total amount and differences in base types, which leads to our differences. For example, the total length of DNA in a normal human cell is 3 billion base pairs, zebrafish is 1.5 billion base pairs, and yeast is only 12 million base pairs.

Faced with such a huge combination of base sequences, scientists began to wonder, are these base sequences really arranged randomly? Or is there a pattern? Are all the sequences on the entire DNA playing a role?

Scientists tried to study these sequences, and the real concept of gene was born. At the beginning, researchers found that not all sequences in our DNA are the same. Some sequences always appear frequently and show some regularities. After repeated summaries, they named some very regular sequences. These base sequences often start and end regularly, and they have an important feature, which is that they can be transcribed into RNA with the help of transcriptase and finally translated into protein.

So scientists formally defined it as a gene.

Gene sequence

(Image source: NIH)

That is to say, in the strict sense of biology, genes refer to sequences that can be transcribed and translated into proteins . And all our genetic information has a corresponding name - genome. The word "group" is also commonly used in biology, and it is generally understood to mean the collection of all.

Of course, scientists soon discovered that this definition was not strict either.

First of all, if defined in this way, genes actually account for a very small proportion of the entire genome. For example, human genes together account for less than 10% of the entire human genome. So what is the rest?

Secondly, if a DNA sequence only produces polypeptides (a primary structure of protein) or even only produces RNA, but this RNA also has a function, is it a gene?

Again, many times the production of a protein may require multiple fragments to act simultaneously. Do they belong to one gene or multiple genes?

Don't underestimate these questions, they will have a very significant impact in the future. Therefore, the definition of gene is still very vague. For biomedical researchers, gene often refers to the entire nucleotide sequence required to produce a polypeptide chain or functional RNA, while for others, gene has different meanings depending on the context.

For example, when we say "the differences between humans and animals are determined by genes", genes refer to the genome; and when we say "blushing due to drinking is determined by genes", genes may refer to the mutation of a certain base.

From this we can see that the concept of gene is really complicated, and there is no complete conclusion yet. So when we talk about genes, it is best to clarify what concept of genes we are referring to.

Now that we understand the concept of genes, what is the genome? What is its significance? Let’s talk about it in the next article.

Editor: Sun Chenyu