📚 Genes and Mutations | 基因与突变
Genes are the fundamental units of heredity, composed of specific sequences of DNA that encode the instructions for building proteins or functional RNA molecules. Mutations are permanent alterations in the nucleotide sequence of the genome. Understanding how genes are structured and how mutations arise is central to A-Level Biology, as it explains both the stability of genetic information and the origin of variation that drives evolution and causes genetic diseases.
基因是遗传的基本单位，由特定的DNA序列组成，编码蛋白质或功能性RNA分子的指令。突变是基因组核苷酸序列的永久性改变。理解基因的结构以及突变如何产生是A-Level生物学的核心内容，因为它既解释了遗传信息的稳定性，也说明了驱动进化和导致遗传疾病的变异来源。
1. The Structure of Genes | 基因的结构
A gene consists of a specific sequence of nucleotides that includes regulatory regions, a coding sequence, and termination signals. In eukaryotes, the coding region is often interrupted by non-coding stretches called introns, which are removed during RNA processing, leaving the exons to be joined together to form mature mRNA.
基因由特定的核苷酸序列组成，包括调控区、编码序列和终止信号。在真核生物中，编码区常常被称为内含子的非编码片段所打断，内含子在RNA加工过程中被移除，剩下的外显子连接起来形成成熟的mRNA。
The promoter region, which lies upstream of the coding sequence, contains specific base sequences such as the TATA box that serve as binding sites for transcription factors and RNA polymerase. This ensures that transcription begins at the correct position and at the appropriate rate. Downstream, the terminator sequence signals the end of transcription.
位于编码序列上游的启动子区含有特定的碱基序列，如TATA盒，这些序列作为转录因子和RNA聚合酶的结合位点，确保转录在正确的位置并以合适的速率起始。下游的终止子序列则发出转录结束的信号。
The genetic code is degenerate, meaning that most amino acids are specified by more than one triplet codon. This property has important implications for the effect of mutations, as not all nucleotide changes alter the amino acid sequence.
遗传密码具有简并性，即大多数氨基酸由多个三联体密码子编码。这种性质对突变的影响有重要意义，因为并非所有的核苷酸改变都会改变氨基酸序列。
2. Types of Gene Mutations | 基因突变的类型
Gene mutations, also known as point mutations, involve changes in one or a few nucleotides within a gene. The main types are substitution, insertion, and deletion. These can occur spontaneously during DNA replication or be induced by external factors.
基因突变（也称点突变）涉及基因内一个或少数几个核苷酸的改变。主要类型包括替换、插入和删除。这些突变可能在DNA复制过程中自发产生，也可能由外部因素诱导。
The table below summarises the principal categories of small-scale mutations at the nucleotide level:
下表总结了核苷酸水平上小规模突变的主要类别：
| Type (English) | 类型 (中文) | Description (English/中文) |
|---|---|---|
| Substitution | 替换 | One nucleotide is replaced by another. / 一个核苷酸被另一个替换。 |
| Insertion | 插入 | One or more nucleotides are added into the sequence. / 一个或多个核苷酸被插入序列中。 |
| Deletion | 删除 | One or more nucleotides are removed from the sequence. / 一个或多个核苷酸从序列中删除。 |
Insertions and deletions that are not in multiples of three result in a frameshift, which alters the reading frame from the point of mutation onwards, often producing a completely different polypeptide and a premature stop codon.
插入或删除的核苷酸数目如果不是3的倍数，会导致移码，从突变点起改变阅读框，通常会生成完全不同的多肽链并提前出现终止密码子。
3. Substitution Mutations in Detail | 替换突变详解
Substitutions can be classified as transitions (purine to purine, or pyrimidine to pyrimidine) or transversions (purine to pyrimidine, or vice versa). Because of the degenerate nature of the genetic code, a substitution may or may not alter the encoded amino acid.
替换突变可进一步分为转换（嘌呤变嘌呤，或嘧啶变嘧啶）和颠换（嘌呤变嘧啶，或反之）。由于遗传密码的简并性，一个替换可能改变编码的氨基酸，也可能不改变。
A substitution that does not change the amino acid is called a silent mutation. If it causes a different amino acid to be incorporated, it is a missense mutation. A substitution that converts a sense codon into a stop codon is a nonsense mutation, leading to premature termination of translation and usually a non-functional protein.
不改变氨基酸的替换称为沉默突变。如果导致不同的氨基酸被插入，则为错义突变。若替换将一个有义密码子变为终止密码子，则为无义突变，导致翻译提前终止，通常产生无功能的蛋白质。
4. Insertion and Deletion: Frameshift Mutations | 插入与删除：移码突变
When insertions or deletions involve a number of nucleotides that is not a multiple of three, the entire reading frame downstream is shifted. This frameshift dramatically changes the amino acid sequence from the point of mutation onward. The resulting polypeptide is usually truncated due to the early appearance of a stop codon in the new reading frame.
当插入或删除的核苷酸数目不是3的倍数时，下游的整个阅读框发生移位。这种移码从突变点开始剧烈改变氨基酸序列。由于新阅读框中提前出现终止密码子，所产生的多肽通常会缩短。
Even if the insertion or deletion is a multiple of three, the protein may still be affected because one or more amino acids are added or removed, which can impair folding and function. However, the damage is usually less severe than that caused by a frameshift.
即使插入或删除的数目是3的倍数，蛋白质仍可能受到影响，因为一个或多个氨基酸的增加或减少可能损害蛋白质的折叠与功能。不过其损伤通常比移码突变更小。
An example of a disease caused by a deletion is cystic fibrosis, where the most common mutation is a three-nucleotide deletion removing phenylalanine at position 508 (ΔF508) in the CFTR protein. This is not a frameshift but still disrupts protein folding and chloride ion transport.
由删除引起的疾病的一个例子是囊性纤维化，其最常见的突变是三个核苷酸的删除，导致CFTR蛋白第508位的苯丙氨酸缺失（ΔF508）。这不是移码突变，但仍会破坏蛋白质的折叠和氯离子转运。
5. Causes of Mutations | 突变的原因
Mutations can arise spontaneously due to errors in DNA replication, such as base mismatches that escape proofreading by DNA polymerase. Spontaneous chemical changes, like the deamination of cytosine to uracil or the depurination of guanine, can also alter the base sequence if not repaired.
突变可因DNA复制中的错误而自发产生，例如未被DNA聚合酶校对功能纠正的碱基错配。自发的化学变化，如胞嘧啶脱氨基变为尿嘧啶或鸟嘌呤脱嘌呤，若未被修复，也可能改变碱基序列。
Induced mutations are caused by mutagens, which are physical or chemical agents that increase the mutation rate. Physical mutagens include ultraviolet (UV) radiation and ionising radiation such as X-rays and gamma rays. UV light induces the formation of thymine dimers, which distort the DNA helix and block replication and transcription.
诱导突变由诱变剂引起，诱变剂是能提高突变率的物理或化学因素。物理诱变剂包括紫外辐射和电离辐射（如X射线和γ射线）。紫外线诱导胸腺嘧啶二聚体的形成，扭曲DNA双螺旋并阻碍复制和转录。
Chemical mutagens include base analogues (e.g., 5-bromouracil) that are incorporated into DNA in place of normal bases and cause mispairing, and intercalating agents that insert between base pairs and cause insertions or deletions during replication.
化学诱变剂包括碱基类似物（如5-溴尿嘧啶），它们替代正常碱基掺入DNA并引起错配；还包括嵌入剂，它们插入碱基对之间，在复制过程中导致插入或删除。
6. Effects of Mutations: Silent, Missense, Nonsense | 突变的影响：沉默、错义、无义
The effect of a substitution mutation on the final protein depends on the position and the specific change. The table below illustrates the three major outcomes for point mutations in a coding sequence:
替换突变对最终蛋白质的影响取决于突变的位置和具体的改变。下表说明了编码序列中点突变的三种主要结果：
| Type (English) | 类型 (中文) | Consequence / 后果 |
|---|---|---|
| Silent mutation | 沉默突变 | No change in amino acid sequence due to degeneracy of the genetic code. / 因密码子简并性，氨基酸序列不变。 |
| Missense mutation | 错义突变 | One amino acid is replaced by another; may alter protein function depending on the location and chemical difference. / 一个氨基酸被另一个取代；可能改变蛋白质功能，取决于位置和化学差异。 |
| Nonsense mutation | 无义突变 | A stop codon is introduced prematurely, resulting in a truncated, usually non-functional polypeptide. / 提前引入终止密码子，产生截短的、通常无功能的多肽。 |
A missense mutation can be conservative, where the new amino acid has similar chemical properties to the original, or non-conservative, where the properties differ significantly. Non-conservative missense mutations are more likely to disrupt protein structure and function.
错义突变可以是保守的（新氨基酸与原始氨基酸化学性质相似），也可以是非保守的（性质明显不同）。非保守错义突变更有可能破坏蛋白质的结构和功能。
7. Sickle Cell Anaemia: A Case Study | 镰刀型细胞贫血症：案例研究
Sickle cell anaemia is a classic example of a disease caused by a single nucleotide substitution. In the β-globin gene on chromosome 11, the codon GAG is changed to GTG. This alters the sixth amino acid of the β-globin polypeptide from glutamic acid (a hydrophilic amino acid) to valine (a hydrophobic amino acid).
镰刀型细胞贫血症是由单个核苷酸替换引起疾病的经典例子。在第11号染色体的β-珠蛋白基因中，密码子GAG变为GTG，使得β-珠蛋白多肽的第6位氨基酸由谷氨酸（亲水性）变为缬氨酸（疏水性）。
GAG (glutamic acid) → GTG (valine)
The resulting abnormal haemoglobin, haemoglobin S (HbS), tends to polymerise under low oxygen conditions, causing red blood cells to become sickle-shaped. These sickled cells are fragile and can block small blood vessels, leading to anaemia, pain crises, and organ damage.
由此产生的异常血红蛋白——血红蛋白S（HbS）——在低氧条件下容易聚合，使红细胞变成镰刀形。这些镰刀形细胞脆弱且会堵塞小血管，导致贫血、疼痛危象和器官损伤。
Interestingly, individuals heterozygous for the sickle cell allele (HbA/HbS) have some sickle-shaped cells but are generally healthy and possess a degree of resistance to malaria. This heterozygote advantage illustrates how a harmful mutation can be maintained in a population through natural selection in malaria-endemic regions.
有趣的是，镰刀型细胞等位基因的杂合子（HbA/HbS）虽然有一些镰刀形细胞，但通常健康，并对疟疾具有一定的抵抗力。这种杂合子优势说明了在疟疾流行地区，有害突变如何通过自然选择在种群中得以保留。
8. Mutations and Evolution | 突变与进化
Mutations are the primary source of new alleles in a population and are therefore essential for evolution. Without mutations, all individuals would be genetically identical, and there would be no raw material upon which natural selection could act. Beneficial mutations, though rare, can increase an organism’s fitness and become established in the population.
突变是种群中新等位基因的主要来源，因此对进化至关重要。没有突变，所有个体在遗传上将完全相同，自然选择就没有可作用的原材料。有益突变虽然罕见，但能提高生物的适合度并在种群中固定下来。
Most mutations are neutral or slightly deleterious. Neutral mutations accumulate in genomes over time, providing a molecular clock that can be used to study evolutionary relationships. Mutations in regulatory regions can also alter gene expression patterns, contributing to morphological evolution without necessarily changing the protein-coding sequence.
大多数突变是中性的或轻微有害的。中性突变在基因组中随时间积累，提供了一个可用于研究进化关系的分子钟。调控区的突变也能改变基因表达模式，从而在不改变蛋白质编码序列的情况下促进形态进化。
9. Mutagens and Carcinogens | 诱变剂与致癌物
Many mutagens are also carcinogens—agents that can cause cancer. Cancer arises from a series of mutations in genes that control cell division, apoptosis, and DNA repair, such as proto-oncogenes and tumour suppressor genes. For example, mutations in the TP53 gene, which encodes the p53 protein, are found in over half of all human cancers.
许多诱变剂同时也是致癌物——能导致癌症的因素。癌症源于控制细胞分裂、凋亡和DNA修复的基因（如原癌基因和肿瘤抑制基因）中一系列突变的积累。例如，编码p53蛋白的TP53基因的突变在超过一半的人类癌症中被发现。
Chemical carcinogens, such as those in tobacco smoke, can form bulky adducts on DNA that interfere with base pairing. Ionising radiation can cause double-strand breaks, which if repaired incorrectly may lead to large-scale chromosomal rearrangements. Understanding these links reinforces the importance of avoiding exposure to known mutagens.
化学致癌物，如烟草烟雾中的物质，可在DNA上形成加合物，干扰碱基配对。电离辐射可引起双链断裂，如果修复不当可能导致大规模染色体重排。了解这些联系强调了避免接触已知诱变剂的重要性。
10. DNA Repair Mechanisms | DNA修复机制
Cells possess several DNA repair systems that correct different types of damage. Proofreading by DNA polymerase during replication is the first line of defence; it removes incorrectly paired nucleotides immediately after they are added. Mismatch repair enzymes then scan the newly synthesised strand for any errors that escaped proofreading.
细胞拥有多种DNA修复系统，以纠正不同类型的损伤。DNA聚合酶在复制过程中的校对是第一道防线；它会在错误核苷酸添加后立即将其切除。错配修复酶随后扫描新合成的链，寻找逃脱校对的所有错误。
For damage caused by UV light, nucleotide excision repair (NER) removes short single-stranded segments containing thymine dimers, and the gap is filled by DNA polymerase and sealed by DNA ligase. Base excision repair (BER) handles small, non-helix-distorting base lesions, such as those resulting from oxidation or deamination.
对于紫外光引起的损伤，核苷酸切除修复（NER）会切除含有胸腺嘧啶二聚体的短单链片段，由DNA聚合酶填补缺口并由DNA连接酶封口。碱基切除修复（BER）则处理不会导致螺旋扭曲的小的碱基损伤，如氧化或脱氨基引起的改变。
Double-strand breaks are repaired by homologous recombination or non-homologous end joining. Defects in DNA repair genes are associated with increased rates of mutation and cancer predisposition, as seen in conditions such as xeroderma pigmentosum, where NER is defective.
双链断裂通过同源重组或非同源末端连接进行修复。DNA修复基因的缺陷与突变率升高和癌症易感性相关，例如在着色性干皮病中，核苷酸切除修复缺陷使患者对紫外线极度敏感。
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