Recombination Generates Extensive Diversity

KEY CONCEPTS
- The human IgH locus can generate in excess of 10⁴ V_H DJ_H sequences.
- Imprecision of joining and insertion of unencoded nucleotides further increase V_H DJ_H diversity to 10⁸ sequences.
- A recombined V_H DJ_H -C_H chain can be paired with in excess of 10⁴ different recombined V_K J_K -C_K or V_λ J_λ -C_λ chains.
A census of the available V, D, J, and C gene segments provides a measure of the diversity that can be accommodated by the variety of the coding regions carried in the germline. In both the IgH and L chain loci, many V gene segments are linked to a much smaller number of C gene segments.
The human λ locus (chromosome 22) has seven C_λ genes, each preceded by its own J segment (FIGURE 16.10). The mouse λ locus (chromosome 16) is much less diverse. The main difference is that in a mouse there are only two V gene segments, each of which is linked to two J_λ C_λ regions. One of the C segments is a pseudogene (nonfunctional gene). This configuration suggests that the mouse suffered in its evolutionary history a large deletion of most of its germline V_λ gene segments.

FIGURE 1. The lambda family consists of V_λ gene segments and a small number of J_λ -C_λ gene segments.
Both the human κ locus (chromosome 2) and the mouse κ locus (chromosome 6) have only one C gene segment, preceded by six J gene segments (one of them being a pseudogene) (FIGURE
2). The Vκ gene segments occupy a large cluster on the chromosome, upstream of the Cκ region. The human cluster has two regions. Just upstream of the Cκ gene segment a 600-kb region contains the Jκ segments and 40 Vκ gene segments. A gap of 800 kb separates this region from another cluster of 36 V gene segments.

FIGURE 2. The human and mouse Igκ families consist of V_K gene segments and five functional J_K segments linked to a single C_K gene segment. V_K genes include nonfunctional pseudogenes.

The V_H , V_κ , and V_λ gene segments are segregated into families. A family comprises members that share more than 80% amino acid identity. In humans, the V_H locus comprises six V_H families: V_H 1 through V_H 6. V_H 3 and V_H 4 are the largest families, each with more than 10 functional members; V_H 6 is the smallest family, consisting of one member only. In mice, the Vκ locus comprises about 18 Vκ families, which vary in size from 2 to 100 members. Like other families of related genes, related V gene segments form subclusters, which were generated by duplication and divergence of individual ancestral members. Many of the V segments are pseudogenes. Although nonfunctional, some of these may function as donors of partial V sequences in secondary rearrangements.
A given lymphocyte expresses either a κ or a λ chain to be paired with a V_H DJ_H -C_H chain. In humans, about 60% of B cells express κ chains and about 40% express λ. In the mouse, 95% of B cells express a κ chain, presumably because of the reduced number of λ gene segments available.
The single IgH chain locus (human chromosome 14) consists of multiple discrete segments (FIGURE 16.12). The furthest 3′ member of the V_H cluster is separated by only 20 kb from the first D segment. The D segments (30) are spread over approximately 50 kb, followed by the cluster of 6 J_H segments. Over the next 220 kb lie all the C_H genes. In addition to the nine functional C_H genes, there are two pseudogenes. The human IgH locus organization suggests that a Cγ gene was duplicated to generate the Cγ-Cγ-Cε- Cα subcluster, after which the entire subcluster was then tandemly duplicated. The mouse IgH locus (chromosome 12) has more V_H gene segments, fewer D and J segments, and eight (instead of nine) C_H genes.

FIGURE 3. A single gene cluster in humans contains all the information for the IgH chain. Depicted is a schematic map of the human IgH chain locus.
The human IgH locus alone can produce more than 10⁴ different V_H DJ_H sequences by combining 51 V_H genes, 30 D segments, and 6 J_H segments. This degree of diversity is further compounded by the imprecision in the V_H DJ_H joinings, the insertion of unencoded nucleotide (N) additions, and use of multiple D-D segments. By combining any one of more than 50 V gene segments with any 1 of 5 J_K segments the human κ locus has the potential to produce 300 different V_K J _Ksegments. These, however, are conservative estimates, because more diversity is introduced by insertion of untemplated N nucleotides, albeit at lower frequency than in V_H DJ_H .
Further diversity is produced by pairing of the same V_H DJ_H -C chain with different V_K J_K -C_K or V_λ J_λ -C_λ chains. Finally, diversification in individual genes after V_H DJ_H , V_K J_K , and V_λ J_λ recombination occurs by somatic hypermutation (SHM) .

اخر الاخبار

اخبار العتبة العباسية المقدسة

العتبة العباسية المقدسة تواصل تنظيم مجالس العزاء الصباحية بذكرى زيارة عاشوراء

مواكب العزاء تستذكر في التاسع من شهر المحرم شهادة عبدالله الرضيع بن الحسين (عليهما السلام)

العتبة العباسية المقدسة تستذكر تضحيات القاسم بن الحسن (عليهما السلام)

شعبة الحرم الشريف تواصل تنفيذ خطتها الخاصة بشهر المحرّم داخل مرقد أبي الفضل العباس (عليه السلام)

المزيد

الآخبار الصحية

لهذا السبب.. إغلاق 25 مركزًا لعلاج الإدمان في مصر ؟

خلافا للاعتقاد الشائع.. علماء يكشفون أسرار بذور البطيخ ؟!

هذا ما يحدث لجسمك عند تناولك الطماطم بانتظام !

تعرف على أطعمة تسرّع "تعافي الجسم" من حروق الشمس

المزيد

الآخبار التكنلوجية

الثلوج تغطي الصحراء الأكثر جفافا في العالم!

بتلسكوب "ألما".. التقاط صورا غير مسبوقة لبدايات الكون !

هل هاتفك مراقب؟.. 5 علامات خطيرة تكشف التجسس عليك

دبي تطلق أول رحلة تجريبية للتاكسي الجوي

المزيد

مواضيع ذات صلة

Other Attenuated Systems: Operons, Bacillus subtilis and HIV

Coupling Translation to Termination

trp Multiple Secondary Structures in trp Leader RNA

Early Explorations of the Hypersynthesis

The Serendipitous Discovery of trp Enzyme Hypersynthesis

Rapid Induction Capabilities of the trp Operon

The Aromatic Amino Acid Synthetic Pathway and its Regulation

How AraC Protein Loops and Unloops

DNA Looping and Repression of araBAD

Binding Sites of the ara Regulatory Proteins

Endoplasmic Reticulum-Associated Degradation and the Unfolded Protein Response

Protein Folding and Modifications in the Endoplasmic Reticulum